WO2016161347A1 - Combinaisons pour générer une mémoire immunologique spécifique d'une tumeur - Google Patents

Combinaisons pour générer une mémoire immunologique spécifique d'une tumeur Download PDF

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WO2016161347A1
WO2016161347A1 PCT/US2016/025673 US2016025673W WO2016161347A1 WO 2016161347 A1 WO2016161347 A1 WO 2016161347A1 US 2016025673 W US2016025673 W US 2016025673W WO 2016161347 A1 WO2016161347 A1 WO 2016161347A1
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inhibitor
cancer
immunomodulating agent
ibrutinib
ctla
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PCT/US2016/025673
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English (en)
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Betty Y. CHANG
Ssucheng Jeff Hsu
Daniel K. LU
Patrick P. Ng
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Pharmacyclics Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • BTK Bruton's tyrosine kinase
  • BCR cell surface B-cell receptor
  • the immunomodulating agent is an anti-CTLA-4 antibody.
  • the immunomodulating agent is a small molecule or an antibody. In some embodiments, the immunomodulating agent is a small molecule inhibitor. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is a CTLA-4 inhibitor.
  • the CTLA-4 inhibitor is an antibody.
  • the CTLA-4 inhibitor is a monoclonal antibody.
  • the CTLA-4 inhibitor is ipilimumab.
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is a CTLA-4 inhibitor.
  • the CTLA-4 inhibitor is an antibody.
  • the CTLA-4 inhibitor is a monoclonal antibody.
  • the CTLA-4 inhibitor is ipilimumab.
  • immunomodulating agent is an inhibitor of TEVI3.
  • the Btk inhibitor is ibrutinib.
  • the administering comprises daily dosing of the
  • the administering comprises dosing of the immunomodulating agent and the Btk inhibitor for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days.
  • the Btk inhibitor is administered once a day, two times per day, three times per day, four times per day, or five times per day.
  • the immunomodulating agent is administered once every five days, once every three days, once every two days, once a day, two times per day, three times per day, four times per day, or five times per day.
  • the Btk inhibitor is administered once per day and the immunomodulating agent is administered every two days.
  • the Btk inhibitor is administered once per day for 27 days and the
  • the immunomodulating agent is administered every two days for 17 days.
  • the Btk inhibitor is administered at a dosage of about 40 mg/day to about 1000 mg/day.
  • the Btk inhibitor is administered orally.
  • the Btk inhibitor and the immunomodulating agent are administered simultaneously, sequentially, or intermittently.
  • the immunomodulating agent is an antibody.
  • the immunomodulating agent is a monoclonal antibody.
  • the immunomodulating agent is ipilimumab.
  • the administering results in an increase in secretion of IFNy and/or an increase in tumor infiltration by Ki67 + / ⁇ + CD4 + and CD8 + T cells.
  • the cancer is a hematological malignancy or a solid tumor. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is metastasized. In some embodiments, the hematological malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a
  • the B-cell malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, FLB lymphoma (DLBCL), mantle cell lymphoma (MCL), Walden
  • the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof.
  • the B- cell malignancy is diffuse large B-cell lymphoma (DLBCL).
  • DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).
  • the B-cell malignancy is a relapsed or refractory B-cell malignancy.
  • the relapsed or refractory B-cell malignancy is diffuse large B-cell lymphoma (DLBCL).
  • the relapsed or refractory DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).
  • the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • B-PLL B cell prolymphocytic leukemia
  • non-CLL/SLL lymphoma mantle cell lymphoma
  • multiple myeloma multiple myeloma
  • Waldenstrom's macroglobulinemia or a combination thereof.
  • the B-cell malignancy is a metastasized B-cell malignancy.
  • the metastasized B-cell malignancy is diffuse large B-cell lymphoma
  • the cancer is a solid tumor.
  • the solid tumor is a sarcoma, or carcinoma.
  • the cancer is selected from anal cancer;
  • bile duct cancer i.e., cholangiocarcinoma
  • bladder cancer breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer;
  • the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the relapsed or refractory cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the metastasized cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the cancer is a colon cancer.
  • the colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell-carcinoma, mucinous
  • the cancer is a breast cancer.
  • the breast cancer is ductal carcinoma in situ, lobular carcinoma in situ, invasive or infiltrating ductal carcinoma, invasive or infiltrating lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma.
  • the method further comprises administering an additional anticancer agent.
  • the additional anticancer agent is selected from among a chemotherapeutic agent, radiation therapy, immunotherapy, or a combination thereof.
  • the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
  • a cancer comprising, administering a CTLA-4 inhibitor and ibrutinib.
  • the administering comprises daily dosing of the CTLA- 4 inhibitor and ibrutinib for at least 7 days.
  • the administering comprises daily dosing of the CTLA-4 inhibitor and ibrutinib for at least 7 days.
  • the administering comprises dosing of the CTLA-4 inhibitor and ibrutinib for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days.
  • the ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day.
  • the CTLA-4 inhibitor is administered once every five days, once every three days, once every two days, once a day, two times per day, three times per day, four times per day, or five times per day.
  • the ibrutinib is administered once per day and CTLA-4 inhibitor is administered every two days.
  • the ibrutinib is administered once per day for 27 days and the CTLA-4 inhibitor is administered every two days for 17 days.
  • ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day. In some embodiments, ibrutinib is administered orally.
  • ibrutinib and the CTLA-4 inhibitor are administered simultaneously, sequentially, or intermittently.
  • the CTLA-4 inhibitor is an antibody.
  • the CTLA-4 inhibitor is a monoclonal antibody.
  • the CTLA-4 inhibitor is ipilimumab.
  • the administering results in an increase in secretion of ⁇ and/or an increase in tumor infiltration by Ki67 + / IFNy CD4 + and CD8 + T cells.
  • the cancer is a hematological malignancy or a solid tumor.
  • the cancer is a relapsed or refractory cancer.
  • the cancer is metastasized.
  • the hematological malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, or a B-cell malignancy.
  • the B- cell malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • FL follicular lymph
  • the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof.
  • the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL).
  • DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC- DLBCL).
  • the B-cell malignancy is a relapsed or refractory B-cell malignancy.
  • the relapsed or refractory B-cell malignancy is diffuse large B-cell lymphoma (DLBCL).
  • the relapsed or refractory DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).
  • the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • B-PLL B cell prolymphocytic leukemia
  • non-CLL/SLL lymphoma mantle cell lymphoma
  • multiple myeloma multiple myeloma
  • Waldenstrom's macroglobulinemia or a combination thereof.
  • the B-cell malignancy is a metastasized B-cell malignancy.
  • the metastasized B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof.
  • the cancer is a solid tumor.
  • the solid tumor is a sarcoma, or carcinoma.
  • the cancer is selected from anal cancer;
  • bile duct cancer i.e., cholangiocarcinoma
  • bladder cancer breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer;
  • the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the relapsed or refractory cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the metastasized cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the cancer is a colon cancer.
  • the colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell-carcinoma, mucinous
  • the cancer is a breast cancer.
  • the breast cancer is ductal carcinoma in situ, lobular carcinoma in situ, invasive or infiltrating ductal carcinoma, invasive or infiltrating lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma.
  • the method further comprises administering an additional anticancer agent.
  • the additional anticancer agent is selected from among a chemotherapeutic agent, radiation therapy, immunotherapy, or a combination thereof.
  • the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.
  • VEGF secretion comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof.
  • the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor.
  • a method of reducing, decreasing, and/or inhibiting angiogenesis comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof.
  • the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor.
  • Figs. 1 A-E exemplify that ibrutinib enhanced the therapeutic efficacy of aCTLA-4 against the A20 B-cell lymphoma.
  • Figs. 2A-2G exemplify that ibrutinib enhanced the therapeutic efficacy of aCTLA-4 against the CT26 colon carcinoma.
  • Fig. 3 exemplifies that aCTLA-4 + ibrutinib generated a robust, tumor- specific immunologic memory.
  • Figs. 4A-4R exemplify that aCTLA-4 + ibrutinib increased tumor infiltration by Ki-67+/IFN-y+ CD4+and CD8+ T cells.
  • Fig. 5 is a schematic of the effect of ibrutinib on the T-cell activation pathway.
  • Figs. 6A-6E show the effect of ibrutinib, either alone or in combination with an immunomodulating agent, in the mouse MBT-bladder cancer model.
  • Fig. 7 shows the effect of ibrutinib, either alone or in combination with an immunomodulating agent, on survival in the mouse MBT-bladder cancer model.
  • Figs. 8A-E show the effect of ibrutinib, either alone or in combination with anti-PD-1 inhibitor, in the mouse MC38 colorectal tumor model.
  • Figs. 9A-9E show the effect of ibrutinib, either alone or in combination with anti-PD-Ll inhibitor, in the mouse MC38 colorectal tumor model.
  • Figs. 10A-E show the effect of ibrutinib, either alone or in combination with anti-CTLA-4 inhibitor, in the mouse MC38 colorectal tumor model.
  • Small molecule Btk inhibitors such as ibrutinib are useful for reducing the risk of or treating a variety of diseases affected by or affecting many cell types of the hematopoietic lineage including, e.g., autoimmune diseases, heteroimmune conditions or diseases, inflammatory diseases, cancer (e.g., B-cell proliferative disorders), and
  • immunomodulating agent in some embodiments, described herein are methods,
  • kits for inducing tumor-specific immunological memory in a cancer which comprises administration of a combination of a Btk inhibitor and a CTLA-4 inhibitor.
  • methods, combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a colon cancer which comprises administration of a combination of a Btk inhibitor and an immunomodulating agent.
  • methods, methods, methods, and kits, for inducing tumor-specific immunological memory in a colon cancer which comprises administration of a combination of a Btk inhibitor and an immunomodulating agent.
  • combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a hematological malignancy which comprises administration of a combination of a Btk inhibitor and an immunomodulating agent.
  • described herein are methods, combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a hematological malignancy, which comprises administration of a combination of a Btk inhibitor and a CTLA-4 inhibitor.
  • acceptable or “pharmaceutically acceptable”, with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.
  • Bioavailability refers to the percentage of ibrutinib dosed that is delivered into the general circulation of the animal or human being studied. The total exposure
  • AUC(O-oo) AUC(O-oo) of a drug when administered intravenously is usually defined as 100% bioavailable (F%).
  • Oral bioavailability refers to the extent to which ibrutinib is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.
  • Blood plasma concentration refers to the concentration of ibrutinib in the plasma component of blood of a subject. It is understood that the plasma concentration of ibrutinib may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood or plasma concentration of ibrutinib may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(O-co)) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of ibrutinib may vary from subject to subject.
  • Cmax maximum plasma concentration
  • Tmax time to reach maximum plasma concentration
  • AUC(O-co) total area under the plasma concentration time curve
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects.
  • An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.
  • the term "therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • an “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of ibrutinib, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.
  • therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition.
  • An "enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in inducing tumor-specific immunological memory in a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • subject refers to an animal.
  • a subject may be, but is not limited to, a mammal including, but not limited to, a human.
  • the terms do not require the supervision (whether continuous or intermittent) of a medical professional.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the terms “treat,” “treating” or “treatment”, include, but are not limited to, prophylactic and/or therapeutic treatments.
  • the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of Btk, in an assay that measures such response.
  • EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • cancer recurrence As used herein, “cancer recurrence”, “cancer relapse”, “relapsed or refractory disease” are used interchangeably herein to refer to a return of cancer following treatment, and includes return of cancer in the primary organ, as well as distant recurrence, where the cancer returns outside of the primary organ.
  • the Btk inhibitor compound described herein i.e. ibrutinib is selective for
  • Btk and kinases having a cysteine residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine 481 in Btk can form a covalent bond with Cys 481 of Btk (e.g., via a Michael reaction).
  • the Btk inhibitor is a compound of Formula (A) having the structure:
  • A is N;
  • Ri is phenyl-O-phenyl or phenyl-S-phenyl
  • R 2 and R 3 are independently H;
  • R4 is L 3 -X-L 4 -G, wherein,
  • L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or
  • L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
  • R6, R-7 and R 8 are independently selected from among H, halogen, CN, OH, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
  • each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
  • two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
  • Rio and Rn can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or each Rii is independently selected from H or substituted or unsubstituted alkyl; or a
  • heterocyclic ring is a piperidine group.
  • G is
  • the compound of Formula (A) is l-[(3R)-3-[4-amino-3-
  • a wide variety of pharmaceutically acceptable salts is formed from ibrutinib and includes:
  • - acid addition salts formed by reacting ibrutinib with an organic acid which includes aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like;
  • - acid addition salts formed by reacting ibrutinib with an inorganic acid which includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.
  • ibrutinib refers to a salt of Ibrutinib, which does not cause significant irritation to a mammal to which it is administered and does not substantially abrogate the biological activity and properties of the compound.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms (solvates).
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like.
  • solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diis
  • solvates are formed using, but limited to, Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • solvates of ibrutinib, or pharmaceutically acceptable salts thereof are conveniently prepared or formed during the processes described herein.
  • solvates of ibrutinib are anhydrous.
  • ibrutinib, or pharmaceutically acceptable salts thereof exist in unsolvated form.
  • ibrutinib, or pharmaceutically acceptable salts thereof exist in unsolvated form and are anhydrous.
  • ibrutinib, or a pharmaceutically acceptable salt thereof is prepared in various forms, including but not limited to, amorphous phase, crystalline forms, milled forms and nano-particulate forms.
  • ibrutinib, or a pharmaceutically acceptable salt thereof is amorphous.
  • ibrutinib, or a pharmaceutically acceptable salt thereof is amorphous and anhydrous.
  • ibrutinib, or a pharmaceutically acceptable salt thereof is crystalline.
  • ibrutinib, or a pharmaceutically acceptable salt thereof is crystalline and anhydrous.
  • ibrutinib is prepared as outlined in U.S. Patent No.
  • the Btk inhibitor is ibrutinib (PCI-32765), PCI-45292,
  • the Btk inhibitor is 4-(tert-butyl)-N-(2-methyl-3-(4- methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)benzamide (CGI-1746); 7-benzyl-l-(3-(piperidin-l-yl)propyl)-2-(4-(pyridin-4- yl)phenyl)-lH-imidazo[4,5-g]quinoxalin-6(5H)-one (CTA-056); (R)-N-(3-(6-(4-(l,4- dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b
  • the Btk inhibitor is:
  • BTK is a member of the Tyrosine-protein kinase (TEC) family of kinases.
  • the TEC family comprises BTK, ITK, TEC, RLK and BMX.
  • a TEC family kinase inhibitor inhibits the kinase activity of BTK, ITK, TEC, RLK and BMX.
  • a TEC family kinase inhibitor is a BTK inhibitor, which is disclosed elsewhere herein.
  • a TEC family kinase inhibitor is an ITK inhibitor.
  • a TEC family kinase inhibitor is a TEC inhibitor.
  • a TEC family kinase inhibitor is a RLK inhibitor.
  • a TEC family kinase inhibitor is a BMK inhibitor.
  • the Itk inhibitor covalently binds to Cysteine 442 of
  • the Itk inhibitor is an Itk inhibitor compound described in WO2002/0500071, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/070420, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/079791, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/076228, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/058832, which is incorporated by reference in its entirety.
  • the Itk inhibitor is an Itk inhibitor compound described in WO2004/016610, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016611, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016600, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016615, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/026175, which is incorporated by reference in its entirety.
  • the Itk inhibitor is an Itk inhibitor compound described in WO2006/065946, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/027594, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/017455, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025820, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025821, which is incorporated by reference in its entirety.
  • the Itk inhibitor is an Itk inhibitor compound described in WO2008/025822, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2011/017219, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2011/090760, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2009/158571, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2009/051822, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in US 13/177657, which is incorporated by reference in its entirety.
  • the Itk inhibitor has a structure selected from:
  • TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor.
  • the TEC inhibitor is a BTK inhibitor or an ITK inhibitor.
  • the TEC inhibitor is a BTK inhibitor.
  • the Btk inhibitor is ibrutinib.
  • the immunotherapeutic agent is an immunomodulating agent.
  • immunomodulating molecules refers to a group of molecules on the cell surface of CD4 and CD8 T cells. In some embodiments, these molecules are activators of T cells. In some embodiments, these molecules effectively serve as "brakes" to down-modulate or inhibit an anti-tumor immune response.
  • Immunomodulating molecules include, but are not limited to, Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collagen
  • Immunomodulating agents refer to any agent that modulates the activity of T cell cell-surface co-inhibitory or co-stimulatory activity.
  • Immunomodulating agents include small molecule inhibitors, antibodies, antibody-derivatives (including Fab fragments and scFvs), antibody-drug conjugates, antisense oligonucleotides, siRNA, aptamers, peptides and peptide mimetics.
  • Inhibitory nucleic acids that decrease the expression and/or activity of immune checkpoint molecules can also be used in the methods disclosed herein.
  • One embodiment is a small inhibitory RNA (siRNA) for interference or inhibition of expression of a target gene.
  • Nucleic acid sequences encoding PD-1, PD-Ll and PD-L2 are disclosed in GENBANK® Accession Nos. NM— 005018, AF344424, NP— 079515, and NP— 054862.
  • a Btk inhibitor e.g., ibrutinib
  • an immunomodulating agent are co-administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially.
  • a Btk inhibitor e.g., ibrutinib
  • an ibrutinib an enzyme that catalyzes the oxidation of a Btk.
  • immunomodulating agent are co-administered in separate dosage forms.
  • ibrutinib and an immunomodulating agent are co-administered in combined dosage forms.
  • a Btk inhibitor e.g., ibrutinib
  • an ibrutinib an enzyme that catalyzes the production of a Btk inhibitor.
  • an ibrutinib e.g., ibrutinib
  • an ibrutinib e.g., ibrutinib
  • an ibrutinib e.g., ibrutinib
  • the immunomodulating agent are administered in separate dosage forms and on separate dosing schedules.
  • the Btk inhibitor e.g., ibrutinib
  • the immunomodulating agent e.g., a CTLA-4 inhibitor
  • the Btk inhibitor functions to suppress the Thl response while enhancing the Th2 response.
  • ibrutinib functions to decrease the number of Th2 polarized T cells in a subject.
  • ibrutinib functions to increase the number of Thl polarized T cells in a subject.
  • ibrutinib functions to increase the number of activated CD8+ cytotoxic T cells in a subject.
  • ibrutinib functions to increase the ratio of Thl polarized T cells to Th2 polarized T cells in a subject.
  • ibrutinib functions to increase IFN- ⁇ expression in a subject.
  • the co-administration of a Btk inhibitor (e.g., ibrutinib) and an immunomodulating agent increases the oral bioavailability of ibrutinib. In some embodiments, the co-administration of ibrutinib and an immunomodulating agent increases the Cmax of ibrutinib. In some embodiments, the co-administration of ibrutinib and an immunomodulating agent increases the AUC of ibrutinib.
  • a Btk inhibitor e.g., ibrutinib
  • an immunomodulating agent increases the oral bioavailability of ibrutinib. In some embodiments, the co-administration of ibrutinib and an immunomodulating agent increases the Cmax of ibrutinib. In some embodiments, the co-administration of ibrutinib and an immunomodulating agent increases the AUC of ibrutinib.
  • co-administration of a Btk inhibitor e.g., ibrutinib
  • an ibrutinib e.g., ibrutinib
  • an ibrutinib e.g., ibrutinib
  • immunomodulating agent does not significantly affect the Tmax or Tl/2 of ibrutinib as compared to the Tmax and Tl/2 of ibrutinib administered without an immunomodulating agent.
  • the daily dosage of a Btk inhibitor when administered in combination with an immunomodulating agent is about 10 mg to about 1000 mg.
  • the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 1
  • the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg to about 140 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg to about 100 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg to about 70 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg.
  • any suitable daily dose of an immunomodulating agent is contemplated for use with the compositions, dosage forms, and methods disclosed herein.
  • Daily dose of the immunomodulating agent depends on multiple factors, the determination of which is within the skills of one of skill in the art.
  • the daily dose of the immunomodulating agent depends of the strength of the immunomodulating agent. Weak immunomodulating agents will require higher daily doses than moderate immunomodulating agents, and moderate immunomodulating agents will require higher daily doses than strong
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO
  • immunomodulating agent is an inhibitory antibody that binds a co-inhibitory molecule or its natural ligand as set forth in Table 1.
  • the immunomodulating agent is an activating antibody that binds a co-stimulatory molecule or its natural ligand as set forth in Table 2. TABLE 2. Co-stimulatory molecules on T cells, NK cells
  • a TEC inhibitor is co-administered with an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (m
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor.
  • the TEC inhibitor is an Itk inhibitor.
  • the Itk inhibitor is co-administered with an
  • immunomodulating agent wherein the immunomodulating agent is an inhibitor of
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II,
  • the Btk inhibitor is co-administered with an
  • immunomodulating agent wherein the immunomodulating agent is an inhibitor of
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody.
  • the immunomodulating agent is a monoclonal antibody.
  • the Btk inhibitor is ibrutinib.
  • ibrutinib is co-administered with an
  • immunomodulating agent wherein the immunomodulating agent is an inhibitor of
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody.
  • the immunomodulating agent is a monoclonal antibody.
  • any suitable immunomodulating agent is contemplated for use with the compositions, dosage forms, and methods disclosed herein. The selection of the
  • immunomodulating agent depends on multiple factors, and the selection of the
  • immunomodulating agent is within the skills of one of skill in the art. For example, factors to be considered include the desired reduction in the daily dose of ibrutinib, any additional drug interactions of the immunomodulating agent, and the length for which the
  • the immunomodulating agent may be taken.
  • the immunomodulating agent is an immunomodulating agent which may be taken long-term, for example chronically.
  • Immunomodulating agents refers to any agent that inhibits the immune checkpoint blockade signal that the immune checkpoint molecule in question regulates.
  • Immunomodulating agents can include, but are not limited to, immune checkpoint molecule binding proteins, antibodies (or fragments or variants thereof) that bind to immune checkpoint molecules, nucleic acids that downregulate expression of the immune checkpoint molecules, or any other molecules that bind to immune checkpoint molecules (i.e. small organic molecules, peptidomimetics, aptamers, etc.).
  • the immunomodulating agent is an antibody.
  • the antibodies for use in the present invention include, but are not limited to, monoclonal antibodies, synthetic antibodies, polyclonal antibodies, multispecific antibodies (including bi- specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, single- chain Fvs (scFv) (including bi-specific scFvs), single chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments of any of the above.
  • antibodies for use in the present invention include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain a binding site for an immune checkpoint molecule that immunospecifically bind to the immune checkpoint molecule.
  • the immunoglobulin molecules for use in the invention can be of any type ⁇ e.g., IgG, IgE, IgM, IgD, IgA and IgY), class ⁇ e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.
  • the antibodies for use in the invention are IgG, more preferably, IgGl.
  • An antibody against an immune checkpoint molecule suitable for use with the methods disclosed herein may be from any animal origin including birds and mammals (e.g., human, murine, donkey, sheep, rabbit, goat, guinea pig, camel, horse, shark or chicken).
  • the antibodies are human or humanized monoclonal antibodies.
  • "human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from mice or other animals that express antibodies from human genes.
  • An antibody against an immune checkpoint molecule suitable for use with the methods disclosed herein may be monospecific, bispecific, trispecific or of greater multispecificity.
  • Multispecific antibodies may immunospecifically bind to different epitopes of a polypeptide or may immunospecifically bind to both a polypeptide as well as a heterologous epitope, such as a heterologous polypeptide or solid support material.
  • the immunomodulating agent is an inhibitor of PD-Ll .
  • the immunomodulating agent is an antibody against PD-Ll . In some embodiments, the immunomodulating agent is a monoclonal antibody against PD-Ll . In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against PD-Ll . In one embodiment, the immunomodulating agent reduces the expression or activity of one or more immune checkpoint proteins, such as PD-Ll . In another embodiment, the immunomodulating agent reduces the interaction between PD-1 and PD-Ll .
  • immunomodulating agents include antibodies (e.g., an anti-PD-Ll antibody), RNAi molecules (e.g., anti-PD-Ll RNAi), antisense molecules (e.g., an anti-PD-Ll antisense RNA), dominant negative proteins (e.g., a dominant negative PD-Ll protein), and small molecule inhibitors.
  • Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.
  • An exemplary anti-PD-Ll antibody includes clone EH12.
  • Exemplary antibodies against PD-Ll include: Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti- PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol- Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; and AstraZeneca's MEDI4736.
  • the anti-PD-Ll antibody is an anti-PD-Ll antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2013079174; CN101104640; WO2010036959; WO2013056716; WO2007005874; WO2010089411; WO2010077634; WO2004004771; WO2006133396; WO201309906; US 20140294898; WO2013181634 or WO2012145493.
  • the PD-Ll inhibitor is a nucleic acid inhibitor of PD-
  • the PD-Ll inhibitor is disclosed in one of the following patent publications (incorporated herein by reference): WO2011127180 or WO2011000841. In some embodiments, the PD-Ll inhibitor is rapamycin.
  • a TEC inhibitor is administered in combination with a
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila),
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a
  • the PD-Ll inhibitor for inducing tumor-specific immunological memory in a cancer.
  • the PD-Ll inhibitor is selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol -Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin.
  • a Btk inhibitor is administered in combination with a PD-Ll inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD- Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin for inducing tumor-specific immunological memory in a cancer.
  • a PD-Ll inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD- Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-
  • ibrutinib is administered in combination with a PD-L1 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • the PD-L1 inhibitor is selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-L1 antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol -Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736;
  • ibrutinib is administered in combination with a PD-L1 inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-L1 antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin for inducing tumor-specific immunological memory in a cancer.
  • a PD-L1 inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-L1 antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS
  • the immunomodulating agent is an inhibitor of PD-L2.
  • the immunomodulating agent is an antibody against PD-L2. In some embodiments, the immunomodulating agent is a monoclonal antibody against PD-L2. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against PD-L2. In some embodiments, the immunomodulating agent reduces the expression or activity of one or more immune checkpoint proteins, such as PD-L2. In other embodiments, the immunomodulating agent reduces the interaction between PD-1 and PD-L2.
  • immunomodulating agents include antibodies (e.g., an anti-PD-L2 antibody), RNAi molecules (e.g., an anti-PD-L2 RNAi), antisense molecules (e.g., an anti-PD-L2 antisense RNA), dominant negative proteins (e.g., a dominant negative PD-L2 protein), and small molecule inhibitors.
  • Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.
  • the PD-L2 inhibitor is GlaxoSmithKline's AMP-224
  • the PD-L2 inhibitor is rHIgM12B7.
  • a TEC inhibitor is administered in combination with a
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a
  • the PD-L2 inhibitor for inducing tumor-specific immunological memory in cancer.
  • the PD-L2 inhibitor is selected from GlaxoSmithKline's AMP-224
  • a BTK inhibitor is administered in combination with a PD-L2 inhibitor selected from GlaxoSmithKline's AMP-224
  • ibrutinib is administered in combination with a PD-L2 inhibitor for inducing tumor-specific immunological memory in cancer.
  • the PD-L2 inhibitor is selected from GlaxoSmithKline's AMP-224
  • ibrutinib is administered in combination with a PD-L2 inhibitor selected from GlaxoSmithKline's AMP-224
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an antibody against PD-1. In some embodiments, the immunomodulating agent is a monoclonal antibody against PD-1. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against PD-1.
  • the inhibitors of PD-1 biological activity disclosed in U.S. Pat. Nos. 7,029,674; 6,808,710; or U.S. Patent Application Nos: 20050250106 and 20050159351 can be used in the methods provided herein.
  • Exemplary antibodies against PD- 1 include: Anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti- mouse PD-1 antibody Clone RMP1-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda,
  • pembrolizumab embrolizumab, lambrolizumab
  • AnaptysBio's anti-PD-1 antibody known as ANBOl 1
  • antibody MDX-1 106 ONO-4538
  • Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab Opdivo®, BMS-936558, MDX1106)
  • AstraZeneca' s AMP-514, and AMP-224 and Pidilizumab (CT-011), CureTech Ltd.
  • the anti-PD-1 antibody is an anti- PD-1 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO014557; WO2011110604; WO2008156712; US2012023752;
  • the PD-1 inhibitor is a PD-1 binding protein as disclosed in WO200914335 (herein incorporated by reference).
  • the PD-1 inhibitor is a peptidomimetic inhibitor of PD-
  • the PD-1 inhibitor is a PD-L1 protein, a PD-L2 protein, or fragments, as well as antibody MDX-1 106 (ONO-4538) tested in clinical studies for inducing tumor-specific immunological memory in certain malignancies (Brahmer et al., J Clin Oncol. 2010 28(19): 3167-75, Epub 2010 Jun 1).
  • Other blocking antibodies may be readily identified and prepared by the skilled person based on the known domain of interaction between PD-1 and PD-L1/PD-L2, as discussed above. For example, a peptide corresponding to the IgV region of PD-1 or PD-L1/PD-L2 (or to a portion of this region) could be used as an antigen to develop blocking antibodies using methods well known in the art.
  • a TEC inhibitor is administered in combination with a
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a
  • the PD-1 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • the PD-1 inhibitor is selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANB011; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP- 514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106
  • BioXcell Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANB011; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD- L2 for inducing tumor-specific immunological memory in a cancer.
  • CT-011 CureTech Ltd
  • MDX-1 106 ONO-4538
  • ibrutinib is administered in combination with a PD-1 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • the PD-1 inhibitor is selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP- 514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD-L2.
  • BioXcell Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD- L2 for inducing tumor-specific immunological memory in a cancer.
  • CT-011 CureTech Ltd
  • MDX-1 106 ONO-45
  • the immunomodulating agent is an inhibitor of CTLA-
  • the immunomodulating agent is an antibody against CTLA-4. In some embodiments, the immunomodulating agent is a monoclonal antibody against CTLA-4. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against CTLA-4. In one embodiment, the anti-CTLA-4 antibody blocks the binding of CTLA-4 to CD80 (B7-1) and/or CD86 (B7-2) expressed on antigen presenting cells.
  • Exemplary antibodies against CTLA-4 include: Bristol Meyers Squibb's anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); and anti-CTLA4 antibody clone BNI3 from Abeam.
  • Anti-CTLA4 antibody clone BNI3 from Abeam.
  • the anti-CTLA-4 antibody is an anti-CTLA-4 antibody disclosed in any of the following patent publications (herein incorporated by reference) :WO 2001014424; WO 2004035607; US2005/0201994; EP 1212422 B 1; WO2003086459;
  • CTLA-4 antibodies are described in U.S. Patent Nos. 5,811,097, 5,855,887, 6,051,227, and 6,984,720; in PCT Publication Nos. WO 01/14424 and WO 00/37504; and in U.S. Publication Nos. 2002/0039581 and 2002/086014; and/or U.S. Patent Nos. 5,977,318, 6,682,736, 7, 109,003, and 7, 132,281, incorporated herein by reference). In some
  • the anti-CTLA-4 antibody is an, for example, those disclosed in: WO 98/42752; U.S. Patent Nos. 6,682,736 and 6,207, 156; Hurwitz et al, Proc. Natl. Acad. Sci. USA, 95(17): 10067-10071 (1998); Camacho et al, J. Clin. Oncol., 22(145): Abstract No. 2505 (2004) (antibody CP- 675206); Mokyr et al, Cancer Res., 58:5301-5304 (1998) (incorporated herein by reference).
  • the CTLA-4 inhibitor is a CTLA-4 ligand as disclosed in WO1996040915.
  • the CTLA-4 inhibitor is a nucleic acid inhibitor of
  • anti-CTLA-4 RNAi molecules may take the form of the molecules described by Mello and Fire in PCT Publication Nos. WO 1999/032619 and WO 2001/029058; U.S. Publication Nos. 2003/0051263, 2003/0055020, 2003/0056235,
  • the anti-CTLA-4 RNAi molecules take the form of double stranded RNAi molecules described by Tuschl in European Patent No. EP 1309726 (incorporated herein by reference).
  • the anti-CTLA-4 RNAi molecules take the form of double stranded RNAi molecules described by Tuschl in U.S. Patent Nos. 7,056,704 and 7,078, 196 (incorporated herein by reference).
  • the CTLA-4 inhibitor is an aptamer described in PCT Publication No.
  • WO2004081021 such as Del 60 or M9- 14 del 55.
  • the anti-CTLA-4 RNAi molecules of the present invention may take the form be RNA molecules described by Crooke in U.S. Patent Nos. 5,898,031, 6, 107,094, 7,432,249, and 7,432,250, and European Application No. EP 0928290
  • a TEC inhibitor is administered in combination with a
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila).
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the BTK inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a
  • the CTLA-4 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • the CTLA-4 inhibitor is selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55.
  • Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab also known as Yervoy®, MDX-010, BMS-734016 and MDX-101
  • anti-CTLA4 Antibody clone 9H10 from Millipore
  • Pfizer' s tremelimumab CP-675,206, ticilimum
  • a Btk inhibitor is administered in combination with a CTLA-4 inhibitor selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55 for inducing tumor-specific
  • a CTLA-4 inhibitor selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, t
  • ibrutinib is administered in combination with a CTLA-
  • the CTLA-4 inhibitor is selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55.
  • Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab also known as Yervoy®, MDX-010, BMS-734016 and MDX-101
  • anti-CTLA-4 Antibody clone 9H10 from Millipore
  • Pfizer' s tremelimumab CP-675,206, ticilimumab
  • anti-CTLA-4 antibody clone BNI3 from Abeam;
  • ibrutinib is administered in combination with a CTLA-4 inhibitor selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55 for inducing tumor-specific
  • a CTLA-4 inhibitor selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206,
  • the immunomodulating agent is an inhibitor of LAG3
  • the immunomodulating agent is an antibody against LAG3. In some embodiments, the immunomodulating agent is a monoclonal antibody against LAG3. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against LAG3. In additional embodiments, an antibody against LAG3 blocks the interaction of LAG3with major histocompatibility complex (MHC) class II molecules.
  • MHC major histocompatibility complex
  • Exemplary antibodies against LAG3 include: anti-Lag-3 antibody clone eBioC9B7W
  • the anti-LAG3 antibody is an anti-LAG3 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2010019570; WO2008132601; or WO2004078928.
  • a TEC inhibitor is administered in combination with a
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila).
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the BTK inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a
  • the LAG3 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • the LAG3 inhibitor is selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG- 3 chimeric antibody A9H12.
  • a Btk inhibitor is administered in combination with a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG- 3 chimeric antibody A9H12 for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a LAG3 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • the LAG3 inhibitor is selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG- 3 chimeric antibody A9H12.
  • ibrutinib is administered in combination with a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; FMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12 for inducing tumor-specific immunological memory in a cancer.
  • a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; FMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12 for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • the immunomodulating agent is a monoclonal antibody against TFM3. In other or additional embodiments, the
  • an antibody against TIM3 blocks the interaction of TIM3 with galectin-9 (Gal9).
  • the anti-TIM3 antibody is an anti-TFM3 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2013006490; WO201155607; WO2011159877; or WO200117057.
  • a TTM3 inhibitor is a TTM3 inhibitor disclosed in WO2009052623.
  • a TEC inhibitor is administered in combination with a
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila).
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a TIM3 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a TIM3 inhibitor for inducing tumor-specific
  • the immunomodulating agent is an antibody against
  • the immunomodulating agent is MGA271.
  • a TEC inhibitor is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for inducing tumor-specific immunological a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a TIM3 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a ⁇ 3 inhibitor for inducing tumor-specific immunological memory in a cancer.
  • a Btk inhibitor is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for inducing tumor-specific
  • ibrutinib is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for inducing tumor-specific
  • the immunomodulating agent is an antibody against
  • the immunomodulating agent is Lirilumab (IPH2101).
  • an antibody against KIR blocks the interaction of KIR with HLA.
  • a TEC inhibitor is administered in combination with a KIR inhibitor (e.g. Lirilumab) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila
  • Therapeutics/Celgene Corporation AVL-291/CC-291 (Avila Therapeutics/Celgene
  • CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a KIR inhibitor (e.g. Lirilumab) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a KIR inhibitor (e.g. Lirilumab) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • CD137 also known as 4-1BB or TNFRSF9.
  • the immunomodulating agent is urelumab (BMS-663513, Bristol-Myers Squibb), PF-05082566 (anti-4-lBB, PF- 2566, Pfizer), or XmAb-5592 (Xencor).
  • an anti-CD137 antibody is an antibody disclosed in U.S. Published Application No. US 2005/0095244; an antibody disclosed in issued U.S. Pat. No. 7,288,638 (such as 20H4.9-IgG4 [10C7 or BMS-663513] or 20H4.9-IgGl [BMS-663031]); an antibody disclosed in issued U.S. Pat. No.
  • the immunomodulating agent is one disclosed in WO 2014036412.
  • an antibody against CD137 blocks the interaction of CD137 with CD137L.
  • a TEC inhibitor is administered in combination with a
  • CD137 inhibitor e.g. urelumab, PF-05082566, XmAb-5592 for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a CD137 inhibitor (e.g. urelumab, PF-05082566, XmAb-5592) for inducing tumor-specific immunological memory in a cancer.
  • a CD137 inhibitor e.g. urelumab, PF-05082566, XmAb-5592
  • ibrutinib is administered in combination with a CD137 inhibitor (e.g. urelumab, PF-05082566, XmAb-5592) for inducing tumor-specific
  • the immunomodulating agent is an antibody against PS.
  • the immunomodulating agent is Bavituximab.
  • a TEC inhibitor is administered in combination with a PS inhibitor (e.g. Bavituximab) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a PS inhibitor (e.g. Bavituximab) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a PS inhibitor (e.g. Bavituximab) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • the immunomodulating agent is alemtuzumab.
  • a TEC inhibitor is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila
  • Therapeutics/Celgene Corporation AVL-291/CC-291 (Avila Therapeutics/Celgene
  • CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • the immunomodulating agent is brentuximab vedotin.
  • an antibody against CD30 blocks the interaction of CD30 with CD30L.
  • a TEC inhibitor is administered in combination with a CD30 inhibitor (e.g. brentuximab vedotin) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene
  • AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation)
  • AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation)
  • AVL-291/CC-291 (Avila
  • CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-08
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a CD30 inhibitor (e.g. brentuximab vedotin) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a CD30 inhibitor (e.g. brentuximab vedotin) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • the immunomodulating agent is gemtuzumab ozogamicin.
  • a TEC inhibitor is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene
  • AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation)
  • AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation)
  • AVL-291/CC-291 (Avila
  • CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-08
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • the immunomodulating agent is ibritumomab tiuxetan. In another embodiment, the immunomodulating agent is ofatumumab. In another embodiment, the immunomodulating agent is rituximab. In another embodiment, the immunomodulating agent is tositumomab.
  • a TEC inhibitor is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor.
  • the TEC inhibitor is a BTK inhibitor.
  • the BTK inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • a BTK inhibitor is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for inducing tumor- specific immunological memory in a cancer.
  • ibrutinib is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • CD27 also known as T FRSF7.
  • the immunomodulating agent is CDX- 1127 (Celldex Therapeutics).
  • an antibody against CD27 blocks the interaction of CD27 with CD70.
  • a TEC inhibitor is administered in combination with a CD27 inhibitor (e.g. CDX-1127) for inducing tumor-specific
  • the TEC inhibitor is a BTK inhibitor or an ITK inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • a BTK inhibitor is administered in combination with a CD27 inhibitor (e.g. CDX-1127) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with an OX40 inhibitor (e.g. CDX- 1127) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an antibody against
  • OX40 also known as T FRSF4 or CD 134.
  • the immunomodulating agent is anti-OX40 mouse IgG.
  • an antibody against OX40 blocks the interaction of OX40 with OX40L.
  • a TEC inhibitor is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for inducing tumor-specific immunological memory in a cancer.
  • GITR Inhibitors e.g. anti-OX40 mouse IgG
  • the immunomodulating agent is an antibody against glucocorticoid-induced tumor necrosis factor receptor (GITR).
  • the immunomodulating agent is TRX518 (GITR, Inc.).
  • an antibody against GITR blocks the interaction of GITR with GITRL.
  • a TEC inhibitor is administered in combination with a GITR inhibitor (e.g. TRX518) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • the BTK inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with a GITR inhibitor (e.g.
  • TRX578 for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with an OX40 inhibitor (e.g. TRX518) for inducing tumor-specific immunological memory in a cancer.
  • OX40 inhibitor e.g. TRX528
  • the immunomodulating agent is an antibody against inducible T-cell COStimulator (ICOS, also known as CD278).
  • the immunomodulating agent is MEDI570 (Medlmmune, LLC) or AMG557 (Amgen).
  • an antibody against ICOS blocks the interaction of ICOS with ICOSL and/or B7-H2.
  • a TEC inhibitor is administered in combination with an ICOS inhibitor (e.g. MEDI570 or AMG557) for inducing tumor-specific immunological memory in a cancer.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila
  • CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-08
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with an ICOS inhibitor (e.g. MEDI570 or AMG557) for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with an OX40 inhibitor (e.g. MEDI570 or AMG557) for inducing tumor-specific immunological memory in a cancer.
  • the immunomodulating agent is an inhibitor against
  • an immunomodulating agent can be one or more binding proteins, antibodies (or fragments or variants thereof) that bind to immune checkpoint molecules, nucleic acids that downregulate expression of the immune checkpoint molecules, or any other molecules that bind to immune checkpoint molecules (i.e. small organic molecules, peptidomimetics, aptamers, etc.).
  • an inhibitor of BTLA CD272
  • an inhibitor of CD 160 is HVEM.
  • an inhibitor of 2B4 is CD48.
  • an inhibitor of LAIRl is collagen.
  • an inhibitor of TIGHT is CD112, CD113, or CD155.
  • an inhibitor of CD28 is CD80 or CD86.
  • an inhibitor of LIGHT is HVEM.
  • an inhibitor of DR3 is TL1 A.
  • an inhibitor of CD226 is CD155 or CD112.
  • an inhibitor of CD2 is CD48 or CD58.
  • SLAM is self inhibitory and an inhibitor of SLAM is SLAM.
  • a TEC inhibitor is administered in combination with an inhibitor against BTLA (CD272), CD160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for inducing tumor-specific immunological memory in a cancer.
  • BTLA CD272
  • CD160 CD160
  • 2B4 LAIRl
  • TIGHT LIGHT
  • DR3, CD226, CD2 SLAM
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila
  • Therapeutics/Celgene Corporation AVL-291/CC-291 (Avila Therapeutics/Celgene
  • CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi
  • the Btk inhibitor is ibrutinib.
  • a Btk inhibitor is administered in combination with an inhibitor against BTLA (CD272), CD 160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for inducing tumor-specific immunological memory in a cancer.
  • ibrutinib is administered in combination with an inhibitor against BTLA (CD272), CD160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for inducing tumor-specific immunological memory in a cancer.
  • BTLA CD272
  • CD160 CD160
  • 2B4 LAIRl
  • TIGHT LIGHT
  • DR3, CD226, CD2 SLAM
  • a method of decreasing VEGF and/or decreasing VEGF secretion comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof.
  • the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor.
  • a method of reducing, decreasing, and/or inhibiting angiogenesis comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof.
  • the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor.
  • methods of inhibiting VEGF are provided. The method comprises the steps of admistering a Btk inhibitor and an immunomodulating agent to an individual in need thereof.
  • VEGF vascular endothelial growth factor
  • tumor and stromal cells including macrophages, endothelial cells and fibroblasts, has multiple functions in the tumor microenvironment.
  • VEGF stimulates vascular endothelial, growth, survival, and proliferation.
  • VEGF is a member of 6 structurally related proteins (VEGF-A; VEGF-B; VEGF-C; VEGF-D; VEGF-E; and placental growth factors.
  • VEGF stimulates angiogenesis, which is a process that involves the ability of VEGF receptors to stimulate signaling pathways that induce the proliferation and migration of endothelial cells, and the ability of these cells to degrade and to remodel the extracellular matrix. These processes cumulate in angiogenesis and formation of new blood vessels.
  • VEGF ligands mediate their angiogenic effects by binding to specific VEGF receptors, leading to
  • VEGF secreted by tumor cells can enhance tumor invasion and survival.
  • a method of inducing tumor- specific immunological memory in a cancer in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent.
  • the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib.
  • the combination provides a synergistic therapeutic effect compared to administration of ibrutinib or the immunomodulating agent alone.
  • the immunomodulating agent is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with PD-L
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-Ll, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-Ll . In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer.
  • a method of inducing tumor- specific immunological memory in an ibrutinib-resistant cancer which comprises
  • a combination comprising: a) ibrutinib; and b) an immunomodulating agent.
  • the combination provides a synergistic therapeutic effect compared to administration of ibrutinib or the immunomodulating agent alone.
  • the immunomodulating agent is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with PD-L
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the ibrutinib-resistant cancer is a solid tumor. In some embodiments, the ibrutinib-resistant cancer is a hematologic cancer.
  • a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent.
  • the solid tumor is a sarcoma or carcinoma.
  • the solid tumor is a sarcoma.
  • the solid tumor is a carcinoma.
  • the sarcoma is selected from alveolar
  • rhabdomyosarcoma alveolar soft part sarcoma; ameloblastoma; angiosarcoma;
  • chondrosarcoma chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;
  • esthesioneuroblastoma Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;
  • hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
  • mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;
  • neoplasms with perivascular epitheioid cell differentiation osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; P ET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma.
  • the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
  • the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.
  • the carcinoma is breast cancer.
  • the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
  • the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is
  • the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the bladder cancer is encompassed by the genitourinary tract cancers.
  • the genitourinary tract cancers also encompass kidney cancer, prostate cancer, and cancers associated with the reproductive organs.
  • the carcinoma is lung cancer.
  • the lung cancer is a non-small cell lung cancer.
  • the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
  • the lung cancer is a small cell lung cancer.
  • the carcinoma is prostate cancer.
  • the prostate cancer is adenocarcinoma or small cell carcinoma.
  • the carcinoma is ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the carcinoma is bile duct cancer.
  • the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing' s bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer.
  • the solid tumor is lung cancer.
  • the solid tumor is colorectal (colon) cancer.
  • the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • the breast cancer is ductal carcinoma in situ
  • the invasive breast carcinoma is further categorized into subtypes.
  • the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.
  • the breast cancer is classified according to stages or how far the tumor cells have spread within the breast tissues and to other portions of the body. In some embodiments, there are five stages of breast cancer, Stage 0-IV. In some embodiments, there are five stages of breast cancer, Stage 0-IV. In some embodiments,
  • Stage 0 breast cancer refers to non-invasive breast cancers or that there are no evidence of cancer cells or abnormal non-cancerous cells breaking out of the origin site.
  • Stage I breast cancer refers to invasive breast cancer in which the cancer cells have invaded into surrounding tissues.
  • Stage I is subclassified into Stage IA and IB, in which Stage IA describes tumor measures up to 2 cm with no spread of cancer cells.
  • Stage IB describes absence of tumor in breast but have small lumps of cancer cells between 0.2mm to 2mm within the lymph nodes.
  • Stage II breast cancer is further subdivided into Stage IIA and IIB.
  • Stage IIA describes tumor between 2cm to 5 cm in breast only, or absence of tumor in breast but with cancer between 2mm to 2cm in axillary lymph nodes.
  • Stage IIB describes tumor larger than 5cm in breast only, or tumor between 2cm to 5 cm in breast with presence of small tumors from 0.2mm to 2mm in axillary lymph nodes.
  • Stage III breast cancer is further subdivided into Stage IIIA, IIIB, and IIIC.
  • Stage IIIA describes absence of tumor or tumor greater than 5cm in breast with small tumors in 4-9 axillary lymph nodes or small tumors 0.2mm-2mm in size in axillary lymph nodes.
  • Stage IIIB describes tumor spreading into the chest wall or skin of the breast causing swelling or ulcer and with presence of tumor in up to 9 axillary lymph nodes.
  • inflammatory breast cancer is also considered as Stage IIIB.
  • Stage IIIC describes absence of tumor or tumor spreading into the chest wall or to the skin of the breast, with tumor present in 10 or more axillary lymph nodes.
  • Stage IV breast cancer refers to invasive breast cancer that has metastasized into the lymph nodes and other portions of the body.
  • the colon cancer is a colorectal cancer.
  • colon cancer is used interchangeably with “colorectal cancer.”
  • colorectal (colon) cancer refers to rectal cancer.
  • the colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, or squamous cell- carcinoma.
  • adenocarcinoma is a mucinous adenocarcinoma or a Signet ring cell adenocarcinoma.
  • the colon cancer is classified according to stages or how far they have spread through the walls of the colon and rectum. In some embodiments, there are five stages of colon cancer, Stage 0-IV. In some embodiments, Stage 0 colon cancer refers to the very early stage of cancer. In some embodiments, Stage I colon cancer refers to when the cancer has spread beyond the innermost lining of the colon to the second and third layers and also involves the inside wall of the colon. In some embodiments, Stage II colon cancer refers to when the tumor has extended through the muscular wall but has not yet spread into the lymph nodes. In some embodiments, Stage III colon cancer refers to when the tumor has metastasized the colon into one or more lymph nodes.
  • Stage IV colon cancer refers to when the tumor has metastasized to other parts of the body.
  • Stage 0 rectal cancer refers to when the tumor is located only on the inner lining of the rectum.
  • Stage I refers to when the tumor has advanced through the inner lining of the rectum but not yet reach past the muscular wall.
  • a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent.
  • the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collagen
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer.
  • the solid tumor is lung cancer.
  • the solid tumor is colorectal (colon) cancer.
  • the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • the immunomodulating agent is an inhibitor of Programmed Death- Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, I
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is colorectal (colon) cancer. In some
  • the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an inhibitor of Programmed Death- Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collagene
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer.
  • the solid tumor is lung cancer.
  • the solid tumor is colorectal (colon) cancer.
  • the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer.
  • the solid tumor is lung cancer.
  • the solid tumor is colorectal (colon) cancer.
  • the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in an ibrutinib-resistant solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274),
  • PD-1 Programmed Death 1
  • CTLA-4 CTLA-4
  • PD-L2 B7-DC, CD273
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the ibrutinib-resistant solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the ibrutinib- resistant solid tumor is prostate cancer.
  • the ibrutinib-resistant solid tumor is breast cancer.
  • the ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the ibrutinib-resistant solid tumor is colorectal (colon) cancer. In some embodiments, the ibrutinib-resistant solid tumor is gastroenterological cancer. In some embodiments, the ibrutinib-resistant solid tumor is melanoma. In some embodiments, the ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the ibrutinib- resistant solid tumor is kidney cancer. In some embodiments, the ibrutinib-resistant solid tumor is head and neck cancer.
  • the ibrutinib-resistant solid tumor is proximal or distal bile duct cancer. In some embodiments, the ibrutinib-resistant solid tumor is alveolar soft part sarcoma. In some embodiments, the ibrutinib-resistant solid tumor is Ewing's bone sarcoma. In some embodiments, the ibrutinib-resistant solid tumor is bladder cancer. In some embodiments, the ibrutinib-resistant solid tumor is ovarian cancer. In some embodiments, the ibrutinib-resistant solid tumor is leiomyosarcoma. In some embodiments, the ibrutinib-resistant solid tumor is osteosarcoma. In some embodiments, the ibrutinib- resistant solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory a breast cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory a colon cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, ⁇ 3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or ⁇ 3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a lung cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, H
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory a prostate cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, ⁇ 3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or ⁇ 3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of ⁇ 3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, H
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory a pancreatic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GIT
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in an ovarian cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of ⁇ 3.
  • described herein is a method of inducing tumor- specific immunological memory in an ovarian cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a bladder cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor-specific immunological memory in a proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a melanoma cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • a cancer is a treatment-naive cancer.
  • a treatment-naive cancer is a cancer that has not been treated by a therapy, such as for example by a TEC inhibitor, an immunomodulating agent, and/or by an additional therapeutic agent disclosed elsewhere herein.
  • a treatment-naive cancer is a solid tumor.
  • a treatment-naive solid tumor is a solid tumor such as bladder, breast, colon, pancreatic, lung, prostate, ovarian, proximal or distal bile duct cancer, or melanoma.
  • described herein is a method of inducing tumor-specific immunological memory in a treatment-naive solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the solid tumor is a relapsed or refractory solid tumor.
  • the relapsed or refractory solid tumor is a sarcoma or carcinoma. In some embodiments, the relapsed or refractory solid tumor is a sarcoma. In some
  • the relapsed or refractory solid tumor is a carcinoma.
  • the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma;
  • ameloblastoma angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;
  • hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
  • mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;
  • neoplasms with perivascular epitheioid cell differentiation osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;
  • the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
  • the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.
  • the carcinoma is breast cancer.
  • the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
  • the carcinoma is pancreatic cancer.
  • the pancreatic cancer is adenocarcinoma, or islet cell carcinoma.
  • the carcinoma is colorectal (colon) cancer.
  • the colorectal cancer is adenocarcinoma.
  • the solid tumor is a colon polyp.
  • the colon polyp is associated with familial adenomatous polyposis.
  • the carcinoma is bladder cancer.
  • the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma.
  • the carcinoma is lung cancer.
  • the lung cancer is a non-small cell lung cancer.
  • the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
  • the lung cancer is a small cell lung cancer.
  • the carcinoma is prostate cancer.
  • the prostate cancer is adenocarcinoma or small cell carcinoma.
  • the carcinoma is ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the carcinoma is bile duct cancer.
  • the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
  • the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer,
  • leiomyosarcoma lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer.
  • the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.
  • the relapsed or refractory solid tumor is a relapsed or refractory breast cancer.
  • the relapsed or refractory breast cancer is ductal carcinoma in situ (intraductal carcinoma), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma.
  • the invasive breast carcinoma is further categorized into subtypes.
  • the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.
  • the relapsed or refractory solid tumor is a relapsed or refractory colon cancer.
  • the relapsed or refractory colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell-carcinoma, mucinous adenocarcinoma, or Signet ring cell adenocarcinoma.
  • a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent.
  • the individual has relapsed or has developed a refractory solid tumor to an existing therapy.
  • the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRT AM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (PD-L1,
  • immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory solid tumor is prostate cancer.
  • the relapsed or refractory solid tumor is breast cancer.
  • the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer.
  • the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of an Itk inhibitor and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (ma
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory solid tumor is prostate cancer.
  • the relapsed or refractory solid tumor is breast cancer.
  • the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer.
  • the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is
  • the relapsed or refractory solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory solid tumor is prostate cancer.
  • the relapsed or refractory solid tumor is breast cancer.
  • the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer.
  • the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory solid tumor is prostate cancer.
  • the relapsed or refractory solid tumor is breast cancer.
  • the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer.
  • the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is
  • the relapsed or refractory solid tumor is
  • the relapsed or refractory solid tumor is neuroblastoma.
  • a relapsed or refractory solid tumor is a relapsed or refractory ibrutinib-resistant solid tumor.
  • described herein is a method of inducing tumor-specific immunological memory in a relapsed or refractory ibrutinib- resistant solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRT AM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (PD-L1,
  • immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the relapsed or refractory ibrutinib-resistant solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory ibrutinib- resistant solid tumor is prostate cancer.
  • the relapsed or refractory ibrutinib-resistant solid tumor is breast cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is colorectal (colon) cancer. In some
  • the relapsed or refractory ibrutinib-resistant solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is melanoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is kidney cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is head and neck cancer.
  • the relapsed or refractory ibrutinib- resistant solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is bladder cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is ovarian cancer.
  • the relapsed or refractory ibrutinib-resistant solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory ibrutinib- resistant solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory breast cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory breast cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • a method of inducing tumor- specific immunological memory in a relapsed or refractory colon cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • a method of inducing tumor- specific immunological memory in a relapsed or refractory colon cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory lung cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory lung cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory prostate cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory prostate cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory pancreatic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory pancreatic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • a method of inducing tumor- specific immunological memory in a relapsed or refractory ovarian cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • a method of inducing tumor- specific immunological memory in a relapsed or refractory ovarian cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory bladder cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory bladder cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene
  • AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation)
  • AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation)
  • AVL-291/CC-291 (Avila
  • CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-08
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, I
  • immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • a method of inducing tumor- specific immunological memory in a relapsed or refractory proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (ma
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory melanoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory melanoma in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • the solid tumor is a metastasized solid tumor.
  • the metastasized solid tumor is a sarcoma or carcinoma.
  • the metastasized solid tumor is a sarcoma.
  • the metastasized solid tumor is a carcinoma.
  • the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma;
  • chondrosarcoma chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;
  • esthesioneuroblastoma Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;
  • hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblasts tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
  • mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;
  • neoplasms with perivascular epitheioid cell differentiation osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;
  • the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
  • the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.
  • the carcinoma is breast cancer.
  • the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
  • the carcinoma is pancreatic cancer.
  • the pancreatic cancer is adenocarcinoma, or islet cell carcinoma.
  • the carcinoma is colorectal (colon) cancer.
  • the colorectal cancer is adenocarcinoma.
  • the solid tumor is a colon polyp.
  • the colon polyp is associated with familial adenomatous polyposis.
  • the carcinoma is bladder cancer.
  • the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma.
  • the carcinoma is lung cancer.
  • the lung cancer is a non-small cell lung cancer.
  • the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
  • the lung cancer is a small cell lung cancer.
  • the carcinoma is prostate cancer.
  • the prostate cancer is adenocarcinoma or small cell carcinoma.
  • the carcinoma is ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the carcinoma is bile duct cancer.
  • the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
  • the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers,
  • the metastasized solid tumor is breast cancer.
  • the metastasized solid tumor is lung cancer.
  • the metastasized solid tumor is ovarian cancer.
  • the metastasized solid tumor is prostate cancer.
  • the metastasized solid tumor is genitourinary tract cancer.
  • the metastasized solid tumor is osteosarcoma.
  • the metastasized solid tumor is leiomyosarcoma. In some embodiments, the metastasized solid tumor is malignant fibrous histiocytoma. In some embodiments, the metastasized solid tumor is alveolar soft part sarcoma. In some
  • the metastasized solid tumor is Ewing's bone sarcomas. In some embodiments, the metastasized solid tumor is melanoma. In some embodiments, the metastasized solid tumor is head and neck cancer. In some embodiments, the metastasized solid tumor is kidney cancer. In some embodiments, the metastasized solid tumor is colorectal cancer. In some embodiments, the metastasized solid tumor is pancreatic cancer. In some embodiments, the metastasized solid tumor is neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an
  • the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (ma
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.
  • a method of inducing tumor- specific immunological memory in a metastasized solid tumor in an individual in need thereof comprises administering a combination of an Itk inhibitor and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, G
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.
  • the metastasized solid tumor is an ibrutinib-resistant solid tumor.
  • described herein is a method of inducing tumor-specific immunological memory in a metastasized ibrutinib-resistant solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the metastasized ibrutinib-resistant solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized breast cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, ⁇ 3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, G
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized colon cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (C
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, G
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized lung cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an
  • the Btk inhibitor is Ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS32
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, G
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • a method of inducing tumor- specific immunological memory in a metastasized prostate cancer in an individual in need thereof comprises administering a combination of a Btk inhibitor and an
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of ⁇ 3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, G
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • a method of inducing tumor- specific immunological memory in a metastasized pancreatic cancer in an individual in need thereof comprises administering a combination of a Btk inhibitor and an
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized pancreatic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized ovarian cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDO 1 , ID02, TD02, A2aR, PD-L 1 , PD- 1 , CTLA-4, LAG3 , or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized ovarian cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1,
  • the MARCO macrophage receptor with collageneous structure
  • MHC class I MHC class II
  • KG2A PS (phosphatidylserine)
  • OX-40 OX40L
  • SLAM TD02
  • TIGHT TL1A
  • VISTA VISTA
  • VTCN1 VTCN1
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized bladder cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-Ll, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-Ll . In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR,
  • PD-Ll also known as B7-H1, CD274
  • PD-1 Programmed Death 1
  • CTLA-4 CTLA-4
  • PD-L2 B7-DC, CD273
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-Ll, PD-1, CTLA-4, LAG3, or TEVI3.
  • the immunomodulating agent is an inhibitor of PD-Ll .
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of a BTK inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila
  • Therapeutics/Celgene Corporation AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (ma
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (ma
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized melanoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in a metastasized melanoma in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof comprises administering a combination of a TEC inhibitor and an immunomodulating agent.
  • the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the hematologic cancer is a T-cell malignancy.
  • the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T- cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma,
  • PTCL-NOS peripheral T-cell lymphoma not otherwise specified
  • anaplastic large cell lymphoma angioimmunoblastic lymphoma
  • ATLL adult T-cell leukemia/lymphoma
  • blastic K-cell lymphoma enteropathy-type T-cell lymphoma
  • hematosplenic gamma-delta T-cell lymphoma hematosplenic gamma-delta
  • lymphoblastic lymphoma nasal K/T-cell lymphomas, or treatment-related T-cell
  • the hematologic cancer is a B-cell proliferative disorder.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
  • the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma
  • DLBCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • AP Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymph
  • DLBCL is further divided into subtypes: activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL.
  • ABC-DLBCL is characterized by a CD79B mutation.
  • ABC-DLBCL is characterized by a CD79A mutation.
  • the ABC- DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof.
  • the cancer is acute or chronic myelogenous (or myeloid) leukemia,
  • myelodysplastic syndrome or acute lymphoblastic leukemia.
  • the cancer is diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the cancer is activated B-cell diffuse large B-cell lymphoma (ABC- DLBCL). In some embodiments, the cancer is follicular lymphoma (FL). In some
  • the cancer is multiple myeloma. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is small lymphocytic lymphoma (SLL). In some embodiments, the cancer is non-CLL/SLL lymphoma. In some embodiments, the cancer is high risk CLL or high risk SLL.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • the cancer is non-CLL/SLL lymphoma. In some embodiments, the cancer is high risk CLL or high risk SLL.
  • a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof comprises administering a combination of a TEC inhibitor and an immunomodulating agent.
  • the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor.
  • the TEC inhibitor is a BTK inhibitor or an ITK inhibitor.
  • the TEC inhibitor is a BTK inhibitor.
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.
  • the immunomodulating agent is an inhibitor of PD-L1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of CTLA-4.
  • the immunomodulating agent is an inhibitor of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the hematologic cancer is a B-cell malignancy.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma
  • DLBCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • AP Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymph
  • the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the hematologic cancer is a B-cell malignancy.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma
  • DLBCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • AP Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymph
  • the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.
  • described herein is a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • Therapeutics/Celgene Corporation AVL-292/CC-292 (Avila Therapeutics/Celgene
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of IDO 1 , ID02, TD02, A2aR, PD-L 1 , PD- 1 , CTLA-4, LAG3 , or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • FL follicular lymphoma
  • DLBCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • AP Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymph
  • the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TEVI4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the hematologic cancer is a B-cell malignancy.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma
  • DLBCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • WLB mantle cell lymphoma
  • MCL mantle cell lymphoma
  • AP Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymph
  • the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.
  • the hematologic cancer is an ibrutinib-resistant hematologic cancer.
  • described herein is a method of inducing tumor- specific immunological memory in an ibrutinib-resistant hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TEVI4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIRl, LIGHT, LTBR
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.
  • the ibrutinib-resistant hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the ibrutinib-resistant hematologic cancer is a B-cell malignancy.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (CLL), small
  • the ibrutinib-resistant hematologic cancer is CLL. In some embodiments, the ibrutinib-resistant hematologic cancer is SLL. In some embodiments, the ibrutinib-resistant hematologic cancer is DLBCL. In some embodiments, the ibrutinib-resistant hematologic cancer is mantle cell lymphoma. In some embodiments, the ibrutinib-resistant hematologic cancer is FL. In some embodiments, the ibrutinib-resistant hematologic cancer is
  • the hematologic cancer is multiple myeloma.
  • the ibrutinib-resistant hematologic cancer is Burkitt's lymphoma.
  • described herein is a method of inducing tumor- specific immunological memory in CLL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in CLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in SLL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in SLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in mantle cell lymphoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila
  • the BTK inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in mantle cell lymphoma in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in DLBCL in an individual in need thereof which comprises administering a combination of a BTK inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene
  • AVL-292/CC-292 Avila Therapeutics/Celgene Corporation
  • AVL-291/CC- 291 Avila Therapeutics/Celgene Corporation
  • CNX 774 Avila Therapeutics
  • BMS-488516 Bristol-Myers Squibb
  • BMS-509744 Bristol-Myers Squibb
  • CGI- 1746 CGI
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TIM3.
  • the DLBCL is ABC-DLBCL, GCB-DLBCL, or DH-DLBCL.
  • described herein is a method of inducing tumor- specific immunological memory in DLBCL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent.
  • the immunomodulating agent is an antibody that binds specifically to
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • LAG3, TIM3, TIM4, 2B4, A2aR B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II,
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • the immunomodulating agent is an inhibitor of TEVI3.
  • the DLBCL is ABC-DLBCL, GCB-DLBCL, or DH-DLBCL.
  • described herein is a method of inducing tumor- specific immunological memory in Waldenstrom's macroglobulinemia in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent.
  • the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,
  • the Btk inhibitor is ibrutinib.
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macro), cytoplasm
  • the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • described herein is a method of inducing tumor- specific immunological memory in Waldenstrom's macroglobulinemia in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ⁇ 4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • immunomodulating agent is an inhibitor of PD-1.
  • the immunomodulating agent is an inhibitor of PD-1.
  • immunomodulating agent is an inhibitor of CTLA-4.
  • the amino acid sequence of CTLA-4 is an inhibitor of CTLA-4.
  • immunomodulating agent is an inhibitor of LAG3.
  • the amino acid sequence of LAG3 is an amino acid sequence of LAG3.
  • immunomodulating agent is an inhibitor of TIM3.
  • a cancer is a treatment-naive cancer.
  • a treatment-naive cancer is a cancer that has not been treated by a therapy, such as for example by a TEC inhibitor, an immunomodulating agent, and/or by an additional therapeutic agent disclosed elsewhere herein.
  • a treatment-naive cancer is a hematologic cancer.
  • described herein is a method of inducing tumor- specific immunological memory in a treatment-naive hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an
  • the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR,
  • the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.
  • the treatment-naive hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the ibrutinib-resistant hematologic cancer is a B-cell malignancy.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (CLL), small
  • the treatment-naive hematologic cancer is CLL. In some embodiments, the treatment-naive hematologic cancer is SLL. In some embodiments, the treatment-naive hematologic cancer is DLBCL. In some embodiments, the treatment-naive hematologic cancer is mantle cell lymphoma. In some embodiments, the treatment-naive hematologic cancer is FL. In some embodiments, the treatment-naive hematologic cancer is
  • the treatment-naive hematologic cancer is multiple myeloma. In some embodiments, the treatment-naive hematologic cancer is Burkitt's lymphoma.
  • the hematologic cancer is a relapsed or refractory hematologic cancer.
  • the relapsed or refractory hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, T- cell malignancy, or a B-cell malignancy.
  • the relapsed or refractory hematologic cancer is a T- cell malignancy.
  • the relapsed or refractory T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T-cell lymphomas.
  • PTCL-NOS peripheral T-cell lymphoma not otherwise specified
  • anaplastic large cell lymphoma angioimmunoblastic lymphoma
  • ATLL adult T-cell leukemia/lymphoma
  • the relapsed or refractory hematologic cancer is a B- cell proliferative disorder.
  • the relapsed or refractory cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non- CLL/SLL lymphoma.
  • the cancer is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's
  • macroglobulinemia multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • PMBL primary mediastinal B-cell lymphoma
  • immunoblastic large cell lymphoma precursor B-lymphoblastic lymphoma
  • B cell prolymphocytic leukemia lymphoplasmacy
  • the relapsed or refractory DLBCL is further divided into subtypes: activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL.
  • ABC- DLBCL is characterized by a CD79B mutation.
  • ABC-DLBCL is characterized by a CD79A mutation.
  • the ABC-DLBCL is
  • the cancer is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.
  • the cancer is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is relapsed or refractory activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the cancer is relapsed or refractory follicular lymphoma (FL). In some embodiments, the cancer is relapsed or refractory multiple myeloma. In some embodiments, the cancer is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is relapsed or refractory small lymphocytic lymphoma (SLL). In some embodiments, the cancer is relapsed or refractory non-CLL/SLL lymphoma. In some embodiments, the cancer is relapsed or refractory high risk CLL or high risk SLL.
  • DLBCL diffuse large B-cell lymphoma
  • a method of inducing tumor- specific immunological memory in a relapsed or refractory hematologic cancer in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent.
  • the individual has relapsed or has developed a refractory hematologic cancer to an existing therapy.
  • the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor.
  • the TEC inhibitor is a Btk inhibitor or an Itk inhibitor.
  • the TEC inhibitor is a Btk inhibitor.
  • the Btk inhibitor is ibrutinib.

Abstract

L'invention concerne des combinaisons d'inhibiteurs de tyrosinekinase de Bruton (Btk), par exemple la 1-((R)-3-(4-amino-3-(4- phénoxyphényl)- 1H-pyrazolo [3,4-d]pyrimidin-1-yl)pipéridin-1-yl)prop-2-èn-1-one, avec un agent immunomodulateur, par exemple, un inhibiteur de CTLA-4. L'invention concerne également des procédés induisant une mémoire immunologique spécifique d'une tumeur dans un cancer par l'administration de combinaisons d'inhibiteurs de tyrosinekinase de Bruton (Btk), par exemple, la 1-((R)-3-(4-amino-3-(4-phénoxyphényl)-1H-pyrazolo [3,4-d] pyrimidin-1-yl)pipéridin-1-yl)prop-2-èn-1-one, et d'un agent immunomodulateur.
PCT/US2016/025673 2015-04-03 2016-04-01 Combinaisons pour générer une mémoire immunologique spécifique d'une tumeur WO2016161347A1 (fr)

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US10954567B2 (en) 2012-07-24 2021-03-23 Pharmacyclics Llc Mutations associated with resistance to inhibitors of Bruton's Tyrosine Kinase (BTK)
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US9885086B2 (en) 2014-03-20 2018-02-06 Pharmacyclics Llc Phospholipase C gamma 2 and resistance associated mutations
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WO2018112364A1 (fr) * 2016-12-16 2018-06-21 Evelo Biosciences, Inc. Polythérapies pour le traitement d'un mélanome
US11229668B2 (en) 2017-02-07 2022-01-25 Nantcell, Inc. Maximizing T-cell memory and compositions and methods therefor

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