WO2023284597A1 - Combined therapy for treating cancer - Google Patents

Combined therapy for treating cancer Download PDF

Info

Publication number
WO2023284597A1
WO2023284597A1 PCT/CN2022/104040 CN2022104040W WO2023284597A1 WO 2023284597 A1 WO2023284597 A1 WO 2023284597A1 CN 2022104040 W CN2022104040 W CN 2022104040W WO 2023284597 A1 WO2023284597 A1 WO 2023284597A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
inhibitor
virus
tumor
pharmaceutical composition
Prior art date
Application number
PCT/CN2022/104040
Other languages
French (fr)
Chinese (zh)
Inventor
何南海
邱庆崇
路杨
杨东晖
Original Assignee
杭州阿诺生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州阿诺生物医药科技有限公司 filed Critical 杭州阿诺生物医药科技有限公司
Priority to CN202280013623.5A priority Critical patent/CN116887837A/en
Publication of WO2023284597A1 publication Critical patent/WO2023284597A1/en

Links

Images

Classifications

    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/761—Adenovirus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/763—Herpes virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/765—Reovirus; Rotavirus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/766—Rhabdovirus, e.g. vesicular stomatitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
    • 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
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a combined treatment method and pharmaceutical composition, comprising administering PI3K inhibitors, oncolytic viruses and PD-1 inhibitors to subjects in need.
  • Immune checkpoint inhibitors using anti-CTLA4 antibodies and anti-PD(L)1 antibodies have brought profound changes to cancer immunotherapy. Since the first immune checkpoint inhibitor (ICI) was approved in 2001, this series of drugs has attracted widespread attention due to their durable clinical effects in complex cancers. However, there are still a large number of cancer patients who do not respond to ICI therapy. So far, the response rate of cancer patients treated with ICI is about 20%, so it is very necessary to find a more effective way of immunotherapy to further use the immune system to treat cancer.
  • the dysregulation of PI3K-AKT-mTOR signaling pathway has a high incidence in cancer patients. It mainly regulates key cellular processes such as cell growth, proliferation, and metabolism, and can promote the survival, expansion and dissemination of cancer cells in cancer patients.
  • the PI3K isoform p110 ⁇ encoded by the PIK3CA gene is the second most mutated proto-oncogene in human cancer.
  • PI3K ⁇ In the PI3K family, PI3K ⁇ is also involved in tumorigenesis, but PI3K ⁇ plays a major role. In addition, the other two isoforms, PI3K ⁇ and PI3K ⁇ , play an important role in regulating the immune system. PI3K ⁇ can regulate and maintain the function of regulatory T cells (Treg), and PI3K ⁇ can not only recruit suppressive myeloid cells into the cancer microenvironment, but also enhance their ability to inhibit the anti-cancer effect of T cells.
  • Treg regulatory T cells
  • the compound of formula I structure (AN2025) and its pharmaceutically acceptable salt are oral pan-I PI3K inhibitors, which are currently in the third phase of clinical research and development, and its indication is head and neck squamous cell carcinoma. It can not only inhibit wild-type PI3 ⁇ , but also inhibit mutant P13K ⁇ , and the mutation sites include H1047R, E542K and E545K. At the same time, it also has inhibitory activity against other PI3K isoforms (PI3K ⁇ , PI3K ⁇ , PI3K ⁇ ).
  • AN2025 has been clinically confirmed that it is effective for the occurrence of breast cancer caused by PI3K/PIK3CA mutations, and the patients with the highest response rate all have PIK3CA mutations (Campone M et al. Eur J Cancer.2018; 103:147-154) .
  • AN2025 can also downregulate the function of Tregs and suppressive myeloid cells and their ability to enter the tumor microenvironment by inhibiting PI3K ⁇ and PI3K ⁇ (O'Donnell JS et al. Semin Cancer Biol. 2018; 48:91-103. Borazanci et al. The Oncol. 2020).
  • Oncolytic viruses are a class of replication-competent tumor-killing viruses. In addition to being able to selectively infect tumor cells and cause tumor cell lysis, oncolytic viruses can also activate the immune response to further kill tumors. On the one hand, tumor cells infected by oncolytic viruses can release a large number of inflammatory factors, activate natural killer cells (NK cells), and initiate the innate immune response to kill tumors. The inflammatory environment can promote the migration of natural killer cells, dendritic cells, and T cells into the tumor microenvironment, making "cold" tumors "hot”.
  • oncolytic viruses lyse tumor cells to produce a large number of tumor-associated antigens, and antigen-presenting cells process and present tumor-associated antigens and virus-associated antigens to T cells to activate adaptive immune responses to kill tumor cells.
  • Pelareorep is a non-pathogenic, naturally occurring, unmodified type 3 reovirus. At present, it is about to enter the third phase of global multi-center clinical trials, and its indication is advanced metastatic breast cancer. In the previous phase II clinical study, Pelareorep combined with paclitaxel in the treatment of advanced/metastatic breast cancer has achieved good experimental results.
  • PDL1 is mainly expressed in immune cells as well as most human cancer cells.
  • cancer PDL1 interacts with PD1 on T cells, ultimately inhibiting the cancer cell-killing activity of T cells.
  • Pelareorep can specifically kill tumor cells in its own unique way, generate an inflammatory tumor microenvironment, promote the infiltration of immune cells into tumor tissue, and turn "cold” tumors into “hot”; AN2025 can systemically regulate the immune suppression The tumor microenvironment, both of which are complementary to the mechanism by which anti-PD(L)1 therapy kills cancer. This triple combination offers an ideal treatment option for most patients with advanced solid tumors.
  • the technical problem to be solved by the present invention is to solve the problem of low response rate of cancer patients treated with ICI in the prior art.
  • the purpose of the present invention is to provide a more effective way of immunotherapy to further utilize the immune system to treat cancer.
  • the present invention provides a method for treating cancer by combining a PI3K inhibitor, an oncolytic virus and a PD-1 inhibitor, and the antitumor activity of the method is significantly better than that of any pairwise combination.
  • the present invention provides the following technical solutions:
  • a method for treating tumor/cancer and/or generating a memory immune response against tumor/cancer in a subject in need thereof comprising administering to said subject an effective amount of a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, wherein, the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be administered simultaneously, separately or sequentially.
  • the PI3K inhibitor is selected from PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ subtype inhibitors.
  • said PI3K inhibitor is selected from Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib , Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof.
  • PI3K inhibitor is a compound having formula (I) or a pharmaceutically acceptable salt thereof
  • the oncolytic virus includes a naturally occurring, modified or recombinant virus capable of replicating and capable of infecting and lysing tumor cells.
  • oncolytic virus is reovirus (reovirus), Newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovirus), vaccinia vaccinia virus, parapox orf virus, Sindbis virus and herpes simplex virus.
  • reovirus reovirus
  • Newcastle disease virus Newcastle disease virus
  • vesicular stomatitis virus vesicular stomatitis virus
  • adenovirus adenovirus
  • vaccinia vaccinia virus parapox orf virus
  • Sindbis virus Sindbis virus and herpes simplex virus.
  • the PD-1 inhibitor is selected from: anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody; preferably, wherein the PD-1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimumab, Sintilimumab, Tislelizumab, Camrelizumab, and any combination thereof.
  • the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be formulated into a dosage form that is taken orally, buccally, or through the parenteral route
  • the dosage form of the oral route can be Tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular , intracranial, intrathecal, intratumoral, transdermal and transmucosal administration, for example, it can be solution, powder injection or lyophilized preparation.
  • the dosage form of the oral route may be tablet, capsule, powder, pill, granule, Suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example, dosage forms for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, Formulations for transdermal and transmucosal administration.
  • the PI3K inhibitor is administered once or twice a day; or every 2, 3, 4, 5, 6, 7, 8, 9, 10 days or every 1, 2 or 3
  • the PI3K inhibitor is administered once a week; or the PI3K inhibitor is administered once a day for 5 consecutive days a week, followed by an interval of 2 days.
  • PI3K inhibitor is used in an adult at a dose of about 20 mg/day to about 200 mg/day, about 30 mg/day to about 160 mg/day, about 60 mg/day to about 120 mg/day Dosage ranges are administered.
  • an effective dose of about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg to administer the PI3K inhibitor to the subject wherein about 0.5 to about 250 mg/kg, about 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg/kg , an effective dose of about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg to administer the PI3K inhibitor to the subject.
  • the dosage form of the oral route can be tablets, capsules, powders, pills, granules, Suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example, dosage forms for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, Formulations for transdermal and transmucosal administration.
  • the oncolytic virus is administered at least once a day, repeated on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21 or 28, or Continuous or intermittent administration of oncolytic virus for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 24 hours or 1-24 hours per day for any period of 2-28 days, or longer. Any time within hours; preferably, the duration of administration is 5, 15, 30, 60, 90, 120, 150 or 180 minutes or any time from 5 to 180 minutes or longer.
  • the dose of the oncolytic virus administered to adults varies according to individual differences (age, body weight, sex), and different administered viruses, for example, about 10 2 -10 17 per person PFU (colony forming units) or TCID 50 (half tissue culture infectious dose) administration.
  • said oncolytic virus is administered to said subject at an effective dose of about 1.0 PFU/kg to about 10 15 PFU/kg.
  • the extradigestive route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, Intratumoral, percutaneous penetration, transmucosal administration.
  • the PD-1 inhibitor is formulated into a solution, a lyophilized agent, or a powder injection.
  • PD-1 inhibitor is administered at an effective dose per kg.
  • said tumor/cancer comprises primary tumor/cancer, recurrent tumor/cancer, or metastatic tumor/cancer, including solid tumors and hematological tumors.
  • said tumor/cancer is selected from the group consisting of: head and neck squamous cell carcinoma, head and neck cancer, brain cancer, glioma, glioblastoma multiforme, neuroblastoma Cell tumor, central nervous system cancer, neuroendocrine tumor, throat cancer, nasopharyngeal cancer, esophageal cancer, thyroid cancer, malignant pleural mesothelioma, lung cancer, breast cancer, liver cancer, hepatoma, hepatobiliary cancer, pancreatic cancer, gastric cancer, Gastrointestinal cancer, bowel cancer, colon cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, melanoma , leukemia, lymphoma, bone cancer, chondrosarcoma, myeloma, multiple myeloma, myelodysplastic syndrome
  • the present invention also provides a pharmaceutical composition and/or a pharmaceutical combination, which comprises a PI3K inhibitor, an oncolytic virus, a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
  • the PI3K inhibitor is selected from PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ subtype inhibitors.
  • the PI3K inhibitor is selected from Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib, Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003 and any combination thereof.
  • the PI3K inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the oncolytic virus includes a naturally occurring, modified or recombinant virus capable of replicating and capable of infecting and lysing tumor cells.
  • oncolytic virus is reovirus (reovirus), Newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovirus), vaccinia virus, parapox orf virus, Sindbis virus and herpes simplex virus.
  • reovirus reovirus
  • Newcastle disease virus Newcastle disease virus
  • vesicular stomatitis virus vesicular stomatitis virus
  • adenovirus adenovirus
  • vaccinia virus parapox orf virus
  • Sindbis virus Sindbis virus and herpes simplex virus
  • the PD-1 inhibitor is selected from: anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody; preferably, wherein the PD
  • the -1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimab, Sintilimumab, Tislelizumab, Camrelizumab, and any combination thereof.
  • the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be in the same and/or separate dosage form.
  • the dosage form of the oral route can be are tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, for example the dosage form for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous,
  • the dosage forms for intramuscular, intracranial, intrathecal, intratumoral, percutaneous penetration, and transmucosal administration can be, for example, solution, powder injection or freeze-dried preparation.
  • the PI3K inhibitor can be formulated into a dosage form that is taken orally, orally, or through an extradigestive route
  • the dosage form of the oral route can be tablets, capsules, Powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, sheath
  • the dosage forms for intratumoral, percutaneous penetration and transmucosal administration can be, for example, solution, powder injection or lyophilized preparation.
  • the oncolytic virus can be formulated into a dosage form that is taken orally, orally, or through an extradigestive route
  • the dosage form of the oral route can be tablets, capsules, Powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, sheath Intratumoral, intratumoral, transdermal, and transmucosal dosage forms.
  • the PD-1 inhibitor can be formulated into a dosage form administered by a parenteral route, for example, the parenteral route can be intravenous, intraperitoneal, intradermal, Subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal, transmucosal administration, for example, can be solution, powder injection or freeze-dried preparation.
  • each unit dosage form contains 1-1000 mg dose of PI3K inhibitor
  • the dose is 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100 , 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000 mg or more A value between any two numeric values.
  • each unit dosage form contains about 10 2 PFU to about 10 17 PFU dose of oncolytic virus, for example, the dose is 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 , 10 15 , 10 16 , 10 17 PFU or any two of TCID 50 or more value between values.
  • each unit dosage form contains a dose of 1-5000 mg of PD-1 inhibitor, for example, the dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2500, 2600, 2700, 2750, 2800, 3000, 3500, 4000, 4500, 5000 mg or a value between any two of the above values.
  • the present invention provides a pharmaceutical composition and/or pharmaceutical combination for treating tumor/cancer and/or generating memory immune response against tumor/cancer.
  • the present invention provides the use of the pharmaceutical composition and/or the pharmaceutical combination for preparing a medicine for treating tumor/cancer and/or generating memory immune response against tumor/cancer.
  • the present invention also provides a kit, which includes the pharmaceutical composition and/or pharmaceutical combination described in the present invention, and instructions for use, wherein the PI3K inhibitor, oncolytic virus and PD-1 inhibitor
  • the agents can be in the same and/or separate containers.
  • FIG. 1 Tumor growth curves of individual EMT6 tumors treated with different drug combinations of AN2025, Pelareorep, and anti-PD-1 antibody. 10 mice per group. AN2025 administration: 30mg/kg, orally (PO) once a day. Pelareorep administration: 2 ⁇ 10 8 TCID 50 administered intravenously once a day for 2 consecutive days, and then stopped for 4 days. Anti-PD-1 antibody administration: 10mg/kg, intravenous injection (IV) once every 6 days.
  • PI3K inhibitor refers to phosphatidylinositol 3-kinase, which is a highly conserved enzyme family and an important part of the intracellular PI3K-Akt-mTOR signaling axis.
  • PI3K inhibitors include, but are not limited to, inhibitors of PI3K alpha, PI3K beta, PI3K gamma, PI3K delta subtypes.
  • Specific examples include, but are not limited to, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib, Bimiralisib, GDC-0084, ACP- 319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof.
  • Preferred examples include, but are not limited to, compounds of formula I as taught herein (also referred to herein as AN2025)
  • oncolytic virus refers to a virus capable of replicating in tumor cells and capable of killing tumor cells. Includes reovirus, Newcastle disease virus, vesicular stomatitis virus, adenovirus, vaccinia virus, parapox orf virus , Sindbis virus and herpes simplex virus.
  • the oncolytic virus includes, but is not limited to, oncolytic viruses of members of the following virus families: myoviridae, siphoviridae, podpviridae, teciviridae ), covering corticoviridae, plasmaviridae, lipothrixviridae, fuselloviridae, poxyiridae, iridoviridae, algal DNA viruses phycodnaviridae, baculoviridae, herpesviridae, adenoviridae, papovaviridae, polydnaviridae, filamentous phages ( inoviridae, microviridae, geminiviridae, circoviridae, parvoviridae, hepadnaviridae, retroviridae, cyst Cyctoviridae, Reoviridae, Birnaviridae, Paramyxoviridae, Rhabdoviridae, Filoviridae, Ortho
  • methods are provided that include immunization against viruses and recombinant viruses of these viruses.
  • the provided methods also include the combined use of at least two oncolytic viruses.
  • the oncolytic virus provided by the method is reovirus. More preferably, the oncolytic virus provided by the method is serotype-3 dearing strain. Examples of oncolytic viruses include, but are not limited to, Onyx-015, DNX-2401, ColoAdl, Oncos102, ProstAtak, CG0070, Pexavec, GLONC1, HF10, HSV1716, Reolysin, and Cavatak.
  • PD-1 inhibitor refers to "anti-PD1/PDL1 antibody", which is an antibody against programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1).
  • exemplary antibodies include, but are not limited to, those shown in Patent Nos. US7,029,674, US7,488,802, US7,521,051, US8,008,449, US8,354,509, US8,617,546, and US8,709,417.
  • PD-1/PD-L1 inhibitors also include Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab Monoclonal antibody and any combination thereof.
  • Treating refers to alleviating, inhibiting and/or reversing the progression of a disease (eg, tumor/cancer) in a subject in need thereof.
  • treatment includes any indication of successful treatment or amelioration of a disease, including any objective or subjective parameter, such as alleviation; palliation; reduction of symptoms or making the injury, pathology or condition more tolerant to the subject; delay or slowing of the rate of progression, and the like. Measures of treatment or improvement may be based, for example, on the results of physical, pathological, and/or diagnostic tests known in the art.
  • the "treatment" of cancer referred to in the present invention refers to the combined treatment of PI3K inhibitors, oncolytic viruses and PD-1 inhibitors of the present invention on cancer or a subject diagnosed with cancer, to At least one positive therapeutic outcome is achieved, such as a decrease in the number of cancer cells, a decrease in tumor size, a decrease in the rate at which tumor cells infiltrate peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth.
  • Treating can also refer to reducing the onset or risk of onset of a disease, or reducing recurrence of a disease (eg, prolonging the time to recurrence) compared to what would occur if the measure were not taken. In the medical field, this treatment is also known as "prophylaxis".
  • an “effective amount” or “therapeutically effective amount” refers to an amount effective to treat a disease, as documented by clinical testing and evaluation, patient observation, and the like.
  • An “effective amount” can further mean an amount that causes a detectable change in biological or chemical activity. A detectable change can be detected and/or further quantified by one skilled in the art familiar with the relevant mechanism or method. Additionally, an “effective amount” can mean an amount that maintains a desired physiological state (ie, reduces or prevents significant decline and/or promotes amelioration of a condition). An “effective amount” can further refer to a therapeutically effective amount.
  • the PI3K inhibitor is administered to a subject in an effective amount.
  • An effective amount is usually 0.01 mg/kg to 500 mg/kg body weight per day.
  • the pharmaceutically acceptable compositions can be formulated so that 0.01 mg/kg body weight to 200 mg/kg body weight or 0.01 mg/kg body weight to 100 mg/kg body weight can be administered to subjects receiving these compositions. Dosage of the compound (for example a dose of 0.75 mg to 7.5 g or 15 g based on a 75 kg human).
  • the active pharmaceutical ingredient of the invention is formulated to provide a dose of 0.01 mg/kg to 70 mg/kg (eg, a dose of 0.75 mg to 5.25 g based on a 75 kg human).
  • the effective dosage of PI3K inhibitor is about 0.5 to about 250 mg/kg, about 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg /kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg.
  • effective doses include about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg, 20 mg/kg , 25mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 75mg/kg, 100mg/kg, 120mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg and 300mg /kg.
  • the dosage form may take various suitable forms, such as tablets or capsules, and the effective dose may be presented in one or more unit dosage forms (such as tablets, capsules) and provided 1, 2 or 3 times a day, or in doses such as 4 , 8 or 12 hour intervals are available throughout the day.
  • Tablets or capsules may contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100 or 1,250 mg of the compound .
  • administering a PI3K inhibitor to a human subject can include a daily dose of the PI3K inhibitor in the range of 100-1,250, 150-1,000, 200-800, or 250-750 mg, the daily dose being It can be administered once a day in its entirety, or in multiple portions at regular intervals throughout the day.
  • Liquid preparations can also be prepared to allow easy and convenient dispensing of any dosage.
  • an oncolytic virus is administered to a subject in an effective dose.
  • the effective dose is determined according to individual differences, and its influencing factors include but not limited to age, sex, body weight and characteristics of the tumor, such as the type and size of the tumor.
  • An effective dose is generally 10 3 -10 12 PFU or TCID 50 for administration to a subject.
  • An effective dose may also be from 1.0 PFU/kg body weight to about 10 15 PFU/kg body weight, for example from 10 2 PFU/kg body weight to 10 13 PFU/kg body weight.
  • the effective dose is about 1 ⁇ 10 8 to 1 ⁇ 10 12 PFU or TCID 50 .
  • an effective dose is about 102 to 1017 PFU.
  • the oncolytic virus can be administered to the subject in a single or multiple doses, and the multiple doses can occur simultaneously or sequentially. For example, administration can last from several days to several weeks.
  • Oncolytic viruses can be administered to one or more tumor sites in the same individual.
  • the dosage form can take various suitable forms, such as administering the oncolytic virus in a dosage form by oral, buccal or parenteral route, and the effective dose can be in one or more unit dosage forms (such as: tablets and capsules) Provided, and provided at least once a day. Tablets and capsules, for example, may contain the oncolytic virus at a dose of about 10 2 PFU to about 10 17 PFU.
  • the dosage is 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 , 10 15 , 10 16 , 10 17 PFU or a value between any two values of TCID 50 or above.
  • Antibodies will generally be mixed with a pharmaceutically acceptable non-toxic carrier substance (such as physiological saline or phosphate buffered saline) prior to administration, and may be administered using any medically appropriate procedure, including, for example, but not Restricted to intravenous or intraarterial administration and injection into cerebrospinal fluid. In some cases, intraperitoneal, intradermal, intracavity, intrathecal, or direct administration to the tumor or an artery supplying the tumor may be advantageous.
  • the effective dosage of the antibody is about 5 to about 250 mg/kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg.
  • effective doses include 5 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 75 mg/kg, 100 mg/kg, 120 mg/kg, 150 mg /kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg and 300mg/kg.
  • Dosage forms may take the form of, for example, tablets or capsules, and an effective dose may be presented in one or more tablets, capsules, etc., and provided once a day or at intervals of, for example, 4, 8 or 12 hours throughout the day.
  • a tablet or capsule may contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 mg of antibody.
  • Liquid preparations can also be prepared to allow easy and convenient dispensing of any dosage.
  • the antibody is administered to a subject in an effective amount.
  • An effective amount is usually 0.01 mg/kg to 500 mg/kg body weight per day.
  • the pharmaceutically acceptable compositions can be formulated so that 0.01 mg/kg body weight to 200 mg/kg body weight or 0.01 mg/kg body weight to 100 mg/kg body weight per day can be administered to patients receiving these compositions. Dosage of the compound (for example a dose of 0.75 mg to 7.5 g or 15 g based on a 75 kg human).
  • compositions of the invention are formulated to provide a dose of 0.01 mg/kg to 70 mg/kg (eg, a dose of 0.75 mg to 5.25 g based on a 75 kg human).
  • An effective amount of the antibody can be, for example, 0.05 mg/kg, 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg or 8 mg/kg per dose (eg doses of 3.75 mg to 600 mg based on a 75 kg human).
  • Doses of the antibody may be administered once, twice, three, four, five or more times, weekly, every two weeks, or even every three weeks during the course of treatment.
  • the dosing time can be once a day, once every two days, once every three days, once every four days, once every five days, once a week, once every two weeks or once every three weeks.
  • Formulations comprising antibodies can be prepared such that any dosage can be dispensed easily and conveniently.
  • subject refers to a mammalian subject, and especially a human subject, including male or female subjects, and including neonatal, infant, toddler, juvenile, adult or elderly subjects, and further includes various races and ethnicities, such as Caucasian, African and Asian.
  • the subject has a tumor/cancer.
  • the tumor patient is a tumor patient with positive expression of PD-L1.
  • pharmaceutically acceptable salt refers to a relatively non-toxic inorganic or organic acid salt of a compound of formula I or formula II of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by reacting the purified compound in free form with a suitable organic or inorganic acid, respectively, and isolating the salt thus formed.
  • Representative acid salts include (but are not limited to) acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate , borate, D-camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconic acid Salt, glucuronate, hexafluorophosphate, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactic acid Salt, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotic acid Salt, oxalate, palmitate, pamoate
  • tumor and cancer are used interchangeably herein to refer to an uncontrolled abnormal growth of a tissue in a localized area of the body. Without timely medical intervention, the tumor/cancer can grow uncontrollably and potentially metastasize to other locations in the body, eventually killing the body.
  • cancer may include cancers caused by genetically inherited mutations.
  • examples of such cancers include, but are not limited to, breast cancer, cancers that may be associated with Li-Frauming syndrome (such as childhood sarcoma, leukemia, and brain cancer), cancers that may be associated with Lynch syndrome such as colon cancer, bile duct cancer, Cancers of the brain, endometrium, kidney, ovary, pancreas, small intestine, stomach and ureter, lung, melanoma, prostate, retinoblastoma, thyroid and uterus.
  • Li-Frauming syndrome such as childhood sarcoma, leukemia, and brain cancer
  • Lynch syndrome such as colon cancer, bile duct cancer
  • cancer can be the result of acquired mutations (such as those caused by diet, environment, and/or lifestyle) or somatic mutations.
  • cancers may include, but are not limited to, adrenal cancer, adrenocortical cancer, bladder cancer, brain cancer, primary brain cancer, glioma, glioblastoma, breast cancer, cervical cancer, colon cancer (non-limiting examples include colorectal cancer, such as colon adenocarcinoma and colon adenoma), endometrial cancer, epithelial cancer, esophageal cancer, gallbladder cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (non- Limiting examples include adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), lymphoma (non-limiting examples include B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma) , mel
  • Metal cancer is cancer in which cancer cells from one organ or body part have spread (by “metastasis”) to another non-adjacent organ or body part. Cancer at a non-adjacent organ or body part (“secondary tumor” or “metastatic tumor”) includes cancer cells originating from an organ or body part where the cancer or cancer cells have spread from that organ or body part. Sites where secondary tumors can occur include, but are not limited to, lymph nodes, lung, liver, brain, and/or bone.
  • pharmaceutically acceptable and “pharmaceutically acceptable” are used interchangeably to refer to the type generally accepted by those skilled in the pharmaceutical arts.
  • pharmaceutically acceptable salts for example, pharmaceutically acceptable salts, pharmaceutically acceptable carriers and the like.
  • Oral dosage form refers to a pharmaceutical formulation prepared for use in an individual by the oral route of administration.
  • known oral dosage forms include, but are not limited to, tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, and the like.
  • powders, pills, granules, capsules and tablets can be coated with suitable polymers or commonly used coating materials to achieve, for example, greater stability in the gastrointestinal tract or to achieve a desired rate of release.
  • the capsule shells of powders, pills or granules are further coated. Tablets may be scored to facilitate dosing division.
  • the films of formula I according to the invention are administered as oral formulations, they are preferably film-coated. Suitable membranes are known in the art and are commercially available or can be manufactured according to known methods.
  • the film coating material is a hydrophilic polymer such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose, among others.
  • the film coating composition ingredients may include plasticizers such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, glycerin in usual amounts; and opacifiers such as titanium dioxide and colorants such as oxidized Iron, aluminum lakes, etc.
  • the film coating material is applied in such an amount as to provide a film coating in the range of 1% to 6% of the solid oral dosage form, for example.
  • crystal fluid When the oncolytic virus of the present invention is administered as an intravenous drip preparation, the following two commonly used fluids can be selected: crystal fluid and colloid fluid.
  • Crystals are aqueous solutions of mineral salts or other water-soluble molecules. Colloids contain larger insoluble molecules such as gelatin; blood itself is a colloid.
  • the most commonly used crystalloid fluid is physiological saline, a 0.9% solution of sodium chloride, which is close to the concentration in blood (isotonic). Ringer's lactic acid or Ringer's acetic acid is another isotonic solution commonly used for large volume fluid replacement.
  • compositions include phosphate buffered saline or other physiologically acceptable buffers, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum powder, calcium phosphate, alginate, baicalin, gelatin , Calcium Silicate, Microcrystalline, Cellulose, Polyvinylpyrrolidone, Cellulose, Sterile Water, Syrup and Methylcellulose.
  • the pharmaceutical composition may also include, but is not limited to, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylparabens; sweetening agents ; and flavoring agents.
  • the terms “comprises” and “including” as used herein have an open and non-limiting meaning.
  • other therapeutic agents such as “biotherapeutic agents” and “chemotherapeutic agents” may also be included.
  • biotherapeutic agent refers to a biomolecule, such as an antibody or a fusion protein, that blocks ligand/receptor activity in any biological pathway that supports tumor maintenance and/or growth or suppresses tumor immune responses.
  • biotherapeutic agents include, but are not limited to: alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab monoclonal antibody, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, nivolumab, a Ticilizumab, Durvalumab, Avelumab.
  • chemotherapeutic agents are chemical compounds that can be used in cancer treatment, including but not limited to alkylating agents, antimetabolites, kinase inhibitors, spindle toxin plant alkaloids, cytotoxic/antitumor biotin, topoiso Constructase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, antisense oligos that inhibit the expression of genes associated with abnormal cell proliferation or tumor growth Nucleotides.
  • chemotherapeutic agents include, but are not limited to, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, Cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, Vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone , bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs,
  • the choice of dosage regimen for the combination therapy of the invention will depend on factors such as: the rate of substantial serum or tissue turnover, the level of symptoms, the overall immunogenicity and the accessibility of the target cells, tissues or organs in the individual being treated.
  • the dosage regimen maximizes the amount of each therapeutic agent delivered to the patient, consistent with acceptable levels of side effects.
  • the dosage and frequency of administration of each biotherapeutic and chemotherapeutic agent in the combination therapy will depend in part on the particular therapeutic agent, the severity of the cancer being treated and the characteristics of the patient.
  • the combination therapy of the invention may be administered before or after surgery to remove the tumor, and may be administered before, during, or after radiation therapy.
  • WO2007084786 specifically describes the compound of formula I of the present invention, the compound or its pharmaceutically acceptable salt and its preparation process are disclosed in the examples of WO2007084786, which is incorporated herein by reference in its entirety.
  • administration of a PI3K inhibitor, an oncolytic virus in combination with a PD-1 inhibitor results in potentiation of the PD-1 inhibitor, making, for example, smaller doses or longer intervals of PD-1 inhibitor therapy possible. It's effective.
  • Antibody includes immunoglobulins of all classes, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, which may be suitable for the medical uses disclosed herein.
  • Antibodies may be monoclonal or polyclonal and may be of any species origin including, for example, mouse, rat, rabbit, horse or human.
  • Antibody fragments that retain specific binding to the protein or epitope (PDL1 or PD1) to which the antibody used in the present invention binds are included within the scope of the term "antibody”. Such fragments can be produced by known techniques.
  • Antibodies can be chimeric or humanized, especially when they are used for therapeutic purposes. Antibodies can be obtained or prepared using methods known in the art.
  • Embodiment 1 The combination therapy of formula I compound (AN2025), oncolytic virus (Pelareorep) and anti-PD-1 antibody treats mouse EMT6 tumor
  • Pelareorep was provided by our company; AN2025 was purchased from MedChem Express. Antibody against mouse PD-1 (clone number: RMP1-14) was purchased from BioXcell.
  • Cell line mouse breast cancer EMT6 cells (CRL-2755) were purchased from American Tissue Culture Center. Cells were cultured in DMEM medium supplemented with 10% fetal bovine serum in an incubator at 37°C and 5% carbon dioxide, and subcultured twice a week until the necessary number of cells for inoculating mice was obtained.
  • mice 6-8 week old BalB/c female mice were purchased from The Jackson Laboratory. Animals were housed in microisolator cages on a 12h light/dark cycle. Cages were changed twice a week. Animals were observed weekly and clinical signs were recorded.
  • mice EMT6 cells cultured in vitro were harvested, suspended in 100 ⁇ l serum-free medium at a cell concentration of 2 ⁇ 10 6 cells/ml, and injected into mice subcutaneously (sc) on the right lower back using a syringe.
  • sc subcutaneously
  • mice were randomly assigned based on tumor size such that the average tumor volume of each group of mice was 76.82 mm 3 .
  • AN2025 administration 30mg/kg, orally (PO) once a day.
  • Pelareorep administration 2 ⁇ 10 8 TCID 50 was given intravenously once a day for 2 consecutive days, and then the medicine was stopped for 4 days, which was used as a dosing cycle for subsequent dosing.
  • RM Repeated measure
  • any pairwise combination of Pelareorep, anti-PD-1 antibody, and AN2025 showed certain anti-tumor activity in the mouse breast cancer EMT6 model.
  • the anti-tumor activity brought about by the combination of Pelareorep, anti-PD-1 antibody and AN2025 was better than any pairwise combination, and was significantly better than the activity of the combination of AN2025 and anti-PD-1 antibody (G5Vs G3, p ⁇ 0.05 ).

Abstract

The present application provides a method for treating a tumor/cancer and/or generating a memory immune response against a tumor/cancer in a subject in such a need, comprising administering to the subject an effective amount of a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, wherein the PI3K inhibitor, the oncolytic virus, and the PD-1 inhibitor can be simultaneously, separately, or sequentially administered. The present application further provides a pharmaceutical composition comprising a PI3K inhibitor, an oncolytic virus, a PD-1 inhibitor, and a pharmaceutically acceptable carrier, and a medicine box comprising the pharmaceutical composition and use description.

Description

用于治疗癌症的组合疗法Combination Therapies Used to Treat Cancer
本申请要求于2021年7月13日提交到中国国家知识产权局的发明名称为“用于治疗癌症的组合疗法”的中国专利申请202110791354.2的优先权，其内容通过引用以整体并入本文。This application claims the priority of Chinese patent application 202110791354.2 filed with the State Intellectual Property Office of China on July 13, 2021, entitled "Combination Therapy for the Treatment of Cancer", the contents of which are hereby incorporated by reference in their entirety.
技术领域technical field
本发明涉及一种组合治疗方法及药物组合物，包括向有需要的对象施用PI3K抑制剂、溶瘤病毒和PD-1抑制剂。The present invention relates to a combined treatment method and pharmaceutical composition, comprising administering PI3K inhibitors, oncolytic viruses and PD-1 inhibitors to subjects in need.
背景技术Background technique
使用抗CTLA4抗体和抗PD(L)1抗体的免疫检查点抑制剂(ICI)给癌症免疫治疗带来了深刻的变革。自从2001年第一个免疫检查点抑制剂(ICI)获批以来，这一系列的药物由于在复杂癌症上持久的临床效果引起了广泛的关注。然而，仍然有大量的癌症患者对于ICI治疗不响应。到目前为止经ICI治疗的癌症患者的响应率约为20％，所以找到一种更加有效的免疫治疗方式来进一步利用免疫***治疗癌症是非常有必要的。Immune checkpoint inhibitors (ICIs) using anti-CTLA4 antibodies and anti-PD(L)1 antibodies have brought profound changes to cancer immunotherapy. Since the first immune checkpoint inhibitor (ICI) was approved in 2001, this series of drugs has attracted widespread attention due to their durable clinical effects in complex cancers. However, there are still a large number of cancer patients who do not respond to ICI therapy. So far, the response rate of cancer patients treated with ICI is about 20%, so it is very necessary to find a more effective way of immunotherapy to further use the immune system to treat cancer.
泛I型P13K抑制剂Pan-type I P13K inhibitors
PI3K-AKT-mTOR信号通路失调在癌症患者中的发生率很高，其主要调控细胞生长，增殖，代谢等关键的细胞过程，在癌症患者中能够促进癌症细胞的存活，扩张和传播。由PIK3CA基因编码的PI3K异构体p110α是人类癌症中排名第二的最容易突变的原癌基因。The dysregulation of PI3K-AKT-mTOR signaling pathway has a high incidence in cancer patients. It mainly regulates key cellular processes such as cell growth, proliferation, and metabolism, and can promote the survival, expansion and dissemination of cancer cells in cancer patients. The PI3K isoform p110α encoded by the PIK3CA gene is the second most mutated proto-oncogene in human cancer.
PI3K家族中，PI3Kβ同样也参与了肿瘤发生，但PI3Kα起着主要作用，除此之外，另外两个异构体PI3Kγ和PI3Kδ则对免疫***起着重要调控作用。PI3Kδ能够调控并维持调节性T细胞(Treg)的功能，PI3Kγ不仅能够募集抑制性的髓系细胞到癌症微环境中，而且能够增强它们对于T细胞抗癌症作用的抑制能力。In the PI3K family, PI3Kβ is also involved in tumorigenesis, but PI3Kα plays a major role. In addition, the other two isoforms, PI3Kγ and PI3Kδ, play an important role in regulating the immune system. PI3Kδ can regulate and maintain the function of regulatory T cells (Treg), and PI3Kγ can not only recruit suppressive myeloid cells into the cancer microenvironment, but also enhance their ability to inhibit the anti-cancer effect of T cells.
式I结构的化合物(AN2025)及其药学上可接受的盐是口服泛I型PI3K抑制剂，目前已经在临床三期研发阶段，其适应症为头颈鳞癌。它不仅能够抑制野生型的PI3α，而且能够抑制突变型的P13Kα，突变位点包括H1047R、E542K和 E545K。同时，其对于其他PI3K异构体(PI3Kβ,PI3Kγ,PI3Kδ)也具有抑制活性。AN2025已经在临床上证实了其对于PI3K/PIK3CA突变导致乳腺癌的发生是有效的，其响应率最高的患者都具有PIK3CA突变(Campone M et al.Eur J Cancer.2018；103:147-154)。AN2025同样可以通过抑制PI3Kδ和PI3Kγ来下调Tregs和抑制性髓系细胞功能以及其进入肿瘤微环境的能力(O'Donnell JS et al.Semin Cancer Biol.2018；48:91-103.Borazanci et al.The Oncol.2020)。The compound of formula I structure (AN2025) and its pharmaceutically acceptable salt are oral pan-I PI3K inhibitors, which are currently in the third phase of clinical research and development, and its indication is head and neck squamous cell carcinoma. It can not only inhibit wild-type PI3α, but also inhibit mutant P13Kα, and the mutation sites include H1047R, E542K and E545K. At the same time, it also has inhibitory activity against other PI3K isoforms (PI3Kβ, PI3Kγ, PI3Kδ). AN2025 has been clinically confirmed that it is effective for the occurrence of breast cancer caused by PI3K/PIK3CA mutations, and the patients with the highest response rate all have PIK3CA mutations (Campone M et al. Eur J Cancer.2018; 103:147-154) . AN2025 can also downregulate the function of Tregs and suppressive myeloid cells and their ability to enter the tumor microenvironment by inhibiting PI3Kδ and PI3Kγ (O'Donnell JS et al. Semin Cancer Biol. 2018; 48:91-103. Borazanci et al. The Oncol. 2020).
Figure PCTCN2022104040-appb-000001
Figure PCTCN2022104040-appb-000001
溶瘤病毒Oncolytic virus
溶瘤病毒是一类具有复制能力的肿瘤杀伤型病毒。除了能够选择性的侵染肿瘤细胞导致肿瘤细胞裂解之外，溶瘤病毒还能够通过激活免疫反应，达到进一步杀伤肿瘤的目的。一方面，溶瘤病毒侵染的肿瘤细胞能够释放大量炎症因子，激活自然杀伤细胞(NK cells)，启动固有免疫反应杀伤肿瘤。炎性环境能够促进自然杀伤细胞，树突状细胞以及T细胞迁移到肿瘤微环境中，使得“冷”肿瘤变“热”。另一方面，溶瘤病毒裂解肿瘤细胞产生大量肿瘤相关抗原，抗原呈递细胞通过加工和呈递肿瘤相关抗原和病毒相关抗原给T细胞，激活获得性免疫反应来杀伤肿瘤细胞。Oncolytic viruses are a class of replication-competent tumor-killing viruses. In addition to being able to selectively infect tumor cells and cause tumor cell lysis, oncolytic viruses can also activate the immune response to further kill tumors. On the one hand, tumor cells infected by oncolytic viruses can release a large number of inflammatory factors, activate natural killer cells (NK cells), and initiate the innate immune response to kill tumors. The inflammatory environment can promote the migration of natural killer cells, dendritic cells, and T cells into the tumor microenvironment, making "cold" tumors "hot". On the other hand, oncolytic viruses lyse tumor cells to produce a large number of tumor-associated antigens, and antigen-presenting cells process and present tumor-associated antigens and virus-associated antigens to T cells to activate adaptive immune responses to kill tumor cells.
Pelareorep是一种非致病的、天然存在的未经修饰的3型呼肠孤病毒。目前其即将进入全球多中心临床三期阶段，其适应症为晚期转移性乳腺癌。在之前的二期临床研究中，Pelareorep联合紫杉醇治疗晚期/转移性乳腺癌，已经取得了良好的实验结果。Pelareorep is a non-pathogenic, naturally occurring, unmodified type 3 reovirus. At present, it is about to enter the third phase of global multi-center clinical trials, and its indication is advanced metastatic breast cancer. In the previous phase II clinical study, Pelareorep combined with paclitaxel in the treatment of advanced/metastatic breast cancer has achieved good experimental results.
抗PD(L)1抗体Anti-PD(L)1 antibody
PD1和PDL1信号通路在调节T细胞激活过程中起到关键作用。PDL1主要在免疫细胞以及大多数的人癌症细胞中表达。在肿瘤微环境中，癌症PDL1与T 细胞上的PD1相互作用，最终抑制T细胞的癌症细胞杀伤活性。大量抗PD(L)1治疗的成功案例，使得它成为现代肿瘤免疫治疗的基石。The PD1 and PDL1 signaling pathways play a key role in regulating T cell activation. PDL1 is mainly expressed in immune cells as well as most human cancer cells. In the tumor microenvironment, cancer PDL1 interacts with PD1 on T cells, ultimately inhibiting the cancer cell-killing activity of T cells. A large number of successful cases of anti-PD(L)1 therapy make it the cornerstone of modern tumor immunotherapy.
Pelareorep能够通过其自身特有的方式特异性的杀伤肿瘤细胞，产生炎性肿瘤微环境，促进免疫细胞浸润到肿瘤组织中，使得“冷”肿瘤变“热”；AN2025能够***性地调节免疫抑制的肿瘤微环境，这两者与抗PD(L)1治疗杀伤癌症的机制是互补的。这种三联组合为大多数晚期实体瘤患者提供了理想的治疗选择。Pelareorep can specifically kill tumor cells in its own unique way, generate an inflammatory tumor microenvironment, promote the infiltration of immune cells into tumor tissue, and turn "cold" tumors into "hot"; AN2025 can systemically regulate the immune suppression The tumor microenvironment, both of which are complementary to the mechanism by which anti-PD(L)1 therapy kills cancer. This triple combination offers an ideal treatment option for most patients with advanced solid tumors.
发明内容Contents of the invention
本发明所要解决的技术问题在于，解决现有技术中经ICI治疗的癌症患者的响应率低的问题。本发明的目的在于提供了一种更加有效的免疫治疗方式来进一步利用免疫***治疗癌症。The technical problem to be solved by the present invention is to solve the problem of low response rate of cancer patients treated with ICI in the prior art. The purpose of the present invention is to provide a more effective way of immunotherapy to further utilize the immune system to treat cancer.
鉴于此，本发明提供了一种PI3K抑制剂、溶瘤病毒以及PD-1抑制剂三者联用来治疗癌症的方法，所述方法的抗肿瘤活性显著优于任意两两组合。In view of this, the present invention provides a method for treating cancer by combining a PI3K inhibitor, an oncolytic virus and a PD-1 inhibitor, and the antitumor activity of the method is significantly better than that of any pairwise combination.
具体而言，本发明提供了如下技术方案：Specifically, the present invention provides the following technical solutions:
一种在有此需要的对象***/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的方法，包括向所述对象施用有效量的PI3K抑制剂、溶瘤病毒以及PD-1抑制剂，其中，所述PI3K抑制剂、溶瘤病毒和PD-1抑制剂可以同时、分开或者顺序施用。A method for treating tumor/cancer and/or generating a memory immune response against tumor/cancer in a subject in need thereof, comprising administering to said subject an effective amount of a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, Wherein, the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be administered simultaneously, separately or sequentially.
在本发明的一个实施方案中，其中所述PI3K抑制剂选自PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ亚型抑制剂。In one embodiment of the present invention, wherein the PI3K inhibitor is selected from PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ subtype inhibitors.
在本发明的一个实施方案中，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003和其任意组合。In one embodiment of the present invention, wherein said PI3K inhibitor is selected from Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib , Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof.
在本发明的一个实施方案中，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，In one embodiment of the present invention, wherein said PI3K inhibitor is a compound having formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022104040-appb-000002
Figure PCTCN2022104040-appb-000002
在本发明的一个实施方案中，其中所述溶瘤病毒包括天然存在的、经过修饰的或经过重组的具有复制能力，并且能够侵染和裂解肿瘤细胞的病毒。In one embodiment of the present invention, the oncolytic virus includes a naturally occurring, modified or recombinant virus capable of replicating and capable of infecting and lysing tumor cells.
在本发明的一个实施方案中，其中溶瘤病毒的选择为呼肠病毒(reovirus)，新城疫病毒(Newcastle disease virus)，水泡性口炎病毒(vesicular stomatitis virus)，腺病毒(adenovirus)，痘苗病毒(vaccinia virus)，滤过性病毒(parapox orf virus)，辛德比斯病毒(Sindbis virus)和单纯疱疹病毒(herpes simplex virus)。In one embodiment of the present invention, wherein the selection of oncolytic virus is reovirus (reovirus), Newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovirus), vaccinia vaccinia virus, parapox orf virus, Sindbis virus and herpes simplex virus.
在本发明的一个实施方案中，其中所述PD-1抑制剂选自：抗PD-1抗体、抗PD-L1抗体和抗PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗和其任意组合物。In one embodiment of the present invention, wherein the PD-1 inhibitor is selected from: anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody; preferably, wherein the PD-1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimumab, Sintilimumab, Tislelizumab, Camrelizumab, and any combination thereof.
在本发明的一个实施方案中，所述PI3K抑制剂、溶瘤病毒和PD-1抑制剂可以配制成以经口服、***或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。In one embodiment of the present invention, the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be formulated into a dosage form that is taken orally, buccally, or through the parenteral route, for example, the dosage form of the oral route can be Tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular , intracranial, intrathecal, intratumoral, transdermal and transmucosal administration, for example, it can be solution, powder injection or lyophilized preparation.
在本发明的一个实施方案中，其中以经口服、***或经消化道外途径的剂型施用所述PI3K抑制剂，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。In one embodiment of the present invention, wherein the PI3K inhibitor is administered in a dosage form of oral, buccal or parenteral route, for example, the dosage form of the oral route may be tablet, capsule, powder, pill, granule, Suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example, dosage forms for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, Formulations for transdermal and transmucosal administration.
在本发明的一个实施方案中，其中每天施用所述PI3K抑制剂1次或2次；或者每2、3、4、5、6、7、8、9、10天或每1、2或3周施用1次所述PI3K抑制剂；或者每周连续5天每天施用1次所述PI3K抑制剂，然后间隔2天。In one embodiment of the present invention, wherein the PI3K inhibitor is administered once or twice a day; or every 2, 3, 4, 5, 6, 7, 8, 9, 10 days or every 1, 2 or 3 The PI3K inhibitor is administered once a week; or the PI3K inhibitor is administered once a day for 5 consecutive days a week, followed by an interval of 2 days.
在本发明的一个实施方案中，其中所述PI3K抑制剂在成年人中以约20mg/天-约200mg/天、约30mg/天-约160mg/天、约60mg/天-约120mg/天的剂量范围施用。In one embodiment of the present invention, wherein said PI3K inhibitor is used in an adult at a dose of about 20 mg/day to about 200 mg/day, about 30 mg/day to about 160 mg/day, about 60 mg/day to about 120 mg/day Dosage ranges are administered.
在本发明的一个实施方案中，其中以约0.5至约250mg/kg、约1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg的有效剂量向所述对象施用所述PI3K抑制剂。In one embodiment of the present invention, wherein about 0.5 to about 250 mg/kg, about 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg/kg , an effective dose of about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg to administer the PI3K inhibitor to the subject.
在本发明的一个实施方案中，其中以经口服、***或经消化道外途径的剂型施用所述溶瘤病毒，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。In one embodiment of the present invention, wherein the oncolytic virus is administered orally, buccally or in a dosage form outside the digestive tract, for example, the dosage form of the oral route can be tablets, capsules, powders, pills, granules, Suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example, dosage forms for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, Formulations for transdermal and transmucosal administration.
在本发明的一个实施方案中，其中每天施用溶瘤病毒至少一次，在第2、3、4、5、6、7、8、9、10、14、21或28天里重复给药，或者任何2-28天时间内，或者更长时间，每天连续或者间断的施用溶瘤病毒1、2、3、4、5、6、7、8、9、10、12或24小时或者1-24小时中的任何时间；优选地，给药持续时间为5、15、30、60、90、120、150或180分钟或者5-180分钟的任何时间或者更长时间。In one embodiment of the invention, wherein the oncolytic virus is administered at least once a day, repeated on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21 or 28, or Continuous or intermittent administration of oncolytic virus for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 24 hours or 1-24 hours per day for any period of 2-28 days, or longer. Any time within hours; preferably, the duration of administration is 5, 15, 30, 60, 90, 120, 150 or 180 minutes or any time from 5 to 180 minutes or longer.
在本发明的一个实施方案中，其中所述溶瘤病毒在成年人中的施用剂量根据个体差异(年龄，体重，性别)，施用病毒的不同而不同，例如以每人约10 2-10 17PFU(菌落形成单位)或者TCID 50(半数组织培养感染剂量)施用。在本发明的一个实施方案中，其中以约1.0PFU/kg至约10 15PFU/kg的有效剂量向所述对象施用所述溶瘤病毒。 In one embodiment of the present invention, the dose of the oncolytic virus administered to adults varies according to individual differences (age, body weight, sex), and different administered viruses, for example, about 10 2 -10 17 per person PFU (colony forming units) or TCID 50 (half tissue culture infectious dose) administration. In one embodiment of the present invention, wherein said oncolytic virus is administered to said subject at an effective dose of about 1.0 PFU/kg to about 10 15 PFU/kg.
在本发明的一个实施方案中，其中以消化道外途径施用所述PD-1抑制剂，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药。In one embodiment of the present invention, wherein the PD-1 inhibitor is administered by an extradigestive route, for example, the extradigestive route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, Intratumoral, percutaneous penetration, transmucosal administration.
在本发明的一个实施方案中，其中所述PD-1抑制剂配制成溶液剂、冻干剂、粉针剂。In one embodiment of the present invention, the PD-1 inhibitor is formulated into a solution, a lyophilized agent, or a powder injection.
在本发明的一个实施方案中，其中以0.05mg/kg、0.1mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg或8mg/kg的有效剂量施用所述PD-1抑制剂。In one embodiment of the present invention, wherein 0.05mg/kg, 0.1mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg or 8mg The PD-1 inhibitor is administered at an effective dose per kg.
在本发明的一个实施方案中，其中所述肿瘤/癌症包括原发肿瘤/癌症，复发肿瘤/癌症，或转移性肿瘤/癌症，包括实体瘤和血液瘤。In one embodiment of the present invention, wherein said tumor/cancer comprises primary tumor/cancer, recurrent tumor/cancer, or metastatic tumor/cancer, including solid tumors and hematological tumors.
在本发明的一个实施方案中，其中所述肿瘤/癌症选自：头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经***癌、神经内分泌肿瘤、咽喉癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝细胞瘤、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子***、膀胱癌、***癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、全身性轻链淀粉样变性和梅克尔细胞癌；更优选的，所述淋巴瘤选自：霍奇金淋巴瘤、非霍奇金淋巴瘤、弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤、富含T-细胞/组织细胞的大B-细胞淋巴瘤和淋巴浆细胞性淋巴瘤，所述肺癌选自：非小细胞肺癌和小细胞肺癌，所述白血病选自：慢性髓细胞样白血病、急性髓细胞样白血病、淋巴细胞白血病、成淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和髓样细胞白血病。In one embodiment of the invention, wherein said tumor/cancer is selected from the group consisting of: head and neck squamous cell carcinoma, head and neck cancer, brain cancer, glioma, glioblastoma multiforme, neuroblastoma Cell tumor, central nervous system cancer, neuroendocrine tumor, throat cancer, nasopharyngeal cancer, esophageal cancer, thyroid cancer, malignant pleural mesothelioma, lung cancer, breast cancer, liver cancer, hepatoma, hepatobiliary cancer, pancreatic cancer, gastric cancer, Gastrointestinal cancer, bowel cancer, colon cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, melanoma , leukemia, lymphoma, bone cancer, chondrosarcoma, myeloma, multiple myeloma, myelodysplastic syndrome, myeloproliferative neoplasms, squamous cell carcinoma, Ewing's sarcoma, systemic light chain amyloidosis and Kerr cell carcinoma; more preferably, the lymphoma is selected from: Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, primary mediastinal large B - cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, T-cell/histiocytic rich large B-cell lymphoma and lymphoplasmacytic lymphoma, said lung cancer being selected from the group consisting of: non-small cell lung cancer and small cell lung cancer selected from the group consisting of chronic myeloid leukemia, acute myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia and myeloid leukemia .
除此之外，本发明还提供了一种药物组合物和/或药物组合，其包含PI3K抑制剂、溶瘤病毒和PD-1抑制剂，以及可药用载体。In addition, the present invention also provides a pharmaceutical composition and/or a pharmaceutical combination, which comprises a PI3K inhibitor, an oncolytic virus, a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂选自PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, the PI3K inhibitor is selected from PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ subtype inhibitors.
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、 Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003和其任意组合。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein the PI3K inhibitor is selected from Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib, Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003 and any combination thereof.
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，In the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein the PI3K inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022104040-appb-000003
Figure PCTCN2022104040-appb-000003
在本发明的药物组合物和/或药物组合中，其中所述溶瘤病毒包括天然存在的、经过修饰的或经过重组的具有复制能力，并且能够侵染和裂解肿瘤细胞的病毒。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, the oncolytic virus includes a naturally occurring, modified or recombinant virus capable of replicating and capable of infecting and lysing tumor cells.
在本发明的药物组合物和/或药物组合中，其中溶瘤病毒的选择为呼肠病毒(reovirus)，新城疫病毒(Newcastle disease virus)，水泡性口炎病毒(vesicular stomatitis virus)，腺病毒(adenovirus)，痘苗病毒(vaccinia virus)，滤过性病毒(parapox orf virus)，辛德比斯病毒(Sindbis virus)和单纯疱疹病毒(herpes simplex virus)。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein the selection of oncolytic virus is reovirus (reovirus), Newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovirus), vaccinia virus, parapox orf virus, Sindbis virus and herpes simplex virus.
在本发明的药物组合物和/或药物组合中，其中所述PD-1抑制剂选自：抗PD-1抗体、抗PD-L1抗体和抗PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗和其任意组合物。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein the PD-1 inhibitor is selected from: anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody; preferably, wherein the PD The -1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimab, Sintilimumab, Tislelizumab, Camrelizumab, and any combination thereof.
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂、溶瘤病毒和PD-1抑制剂可以处于同一和/或分开的剂型(dosage form)中。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be in the same and/or separate dosage form.
在本发明的药物组合物和/或药物组合中，其中所述药物组合物和/或药物组合可以配制成以经口服、***或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液 和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein the pharmaceutical composition and/or pharmaceutical combination can be formulated into a dosage form by oral, buccal or parenteral route, for example, the dosage form of the oral route can be are tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, for example the dosage form for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, The dosage forms for intramuscular, intracranial, intrathecal, intratumoral, percutaneous penetration, and transmucosal administration can be, for example, solution, powder injection or freeze-dried preparation.
在本发明的药物组合物和/或药物组合中，所述PI3K抑制剂可以配制成以经口服、***或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。In the pharmaceutical composition and/or drug combination of the present invention, the PI3K inhibitor can be formulated into a dosage form that is taken orally, orally, or through an extradigestive route, for example, the dosage form of the oral route can be tablets, capsules, Powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, sheath The dosage forms for intratumoral, percutaneous penetration and transmucosal administration can be, for example, solution, powder injection or lyophilized preparation.
在本发明的药物组合物和/或药物组合中，其中所述溶瘤病毒可以配制成经口服、***或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, the oncolytic virus can be formulated into a dosage form that is taken orally, orally, or through an extradigestive route, for example, the dosage form of the oral route can be tablets, capsules, Powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, sheath Intratumoral, intratumoral, transdermal, and transmucosal dosage forms.
在本发明的药物组合物和/或药物组合中，其中所述PD-1抑制剂可以配制成以消化道外途径施用的剂型，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药，例如可以是溶液剂、粉针剂或冻干剂。In the pharmaceutical composition and/or drug combination of the present invention, the PD-1 inhibitor can be formulated into a dosage form administered by a parenteral route, for example, the parenteral route can be intravenous, intraperitoneal, intradermal, Subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal, transmucosal administration, for example, can be solution, powder injection or freeze-dried preparation.
在本发明的药物组合物和/或药物组合中，其中每单位剂型(unit dosage form)中包含1-1000mg剂量的PI3K抑制剂，例如所述剂量为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000mg或以上任意两个数值之间的值。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein each unit dosage form (unit dosage form) contains 1-1000 mg dose of PI3K inhibitor, for example, the dose is 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100 , 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000 mg or more A value between any two numeric values.
在本发明的药物组合物和/或药物组合中，其中每单位剂型(unit dosage form)中包含约10 2PFU至约10 17PFU剂量的溶瘤病毒，例如所述剂量为10 2、10 3、10 4、10 5、10 6、10 7、10 8、10 9、10 10、10 11、10 12、10 13、10 14、10 15、10 16、10 17PFU或者TCID 50或以上任意两个数值之间的值。 In the pharmaceutical composition and/or pharmaceutical combination of the present invention, each unit dosage form (unit dosage form) contains about 10 2 PFU to about 10 17 PFU dose of oncolytic virus, for example, the dose is 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 , 10 15 , 10 16 , 10 17 PFU or any two of TCID 50 or more value between values.
在本发明的药物组合物和/或药物组合中，其中每单位剂型中包含1-5000mg剂量的PD-1抑制剂，例如所述剂量为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000、1100、1200、1300、1400、1500、1600、1700、1800、1900、2000、2200、2400、2500、2600、2700、2750、2800、3000、3500、4000、4500、5000mg或以上任意两个数值之间的值。In the pharmaceutical composition and/or pharmaceutical combination of the present invention, each unit dosage form contains a dose of 1-5000 mg of PD-1 inhibitor, for example, the dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2500, 2600, 2700, 2750, 2800, 3000, 3500, 4000, 4500, 5000 mg or a value between any two of the above values.
本发明提供一种药物组合物和/或药物组合，其用于***/癌症和/或产生针对肿瘤/癌症的记忆免疫应答。The present invention provides a pharmaceutical composition and/or pharmaceutical combination for treating tumor/cancer and/or generating memory immune response against tumor/cancer.
本发明提供药物组合物和/或药物组合用于制备***/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的药物的用途。The present invention provides the use of the pharmaceutical composition and/or the pharmaceutical combination for preparing a medicine for treating tumor/cancer and/or generating memory immune response against tumor/cancer.
除此之外，本发明还提供了一种药盒，其包含本发明所述的药物组合物和/或药物组合，以及使用说明，其中所述PI3K抑制剂、溶瘤病毒和PD-1抑制剂可以处于同一和/或分开的容器中。In addition, the present invention also provides a kit, which includes the pharmaceutical composition and/or pharmaceutical combination described in the present invention, and instructions for use, wherein the PI3K inhibitor, oncolytic virus and PD-1 inhibitor The agents can be in the same and/or separate containers.
附图说明Description of drawings
图1用AN2025、Pelareorep以及抗PD-1抗体的不同药物组合治疗单个EMT6肿瘤的肿瘤生长曲线。每组10只小鼠。AN2025给药：30mg/kg，每天口服(PO)一次。Pelareorep给药：2×10 8TCID 50连续2天每天静脉给药一次，然后停药4天。抗PD-1抗体给药：10mg/kg，每6天静脉注射(IV)一次。 Figure 1. Tumor growth curves of individual EMT6 tumors treated with different drug combinations of AN2025, Pelareorep, and anti-PD-1 antibody. 10 mice per group. AN2025 administration: 30mg/kg, orally (PO) once a day. Pelareorep administration: 2×10 8 TCID 50 administered intravenously once a day for 2 consecutive days, and then stopped for 4 days. Anti-PD-1 antibody administration: 10mg/kg, intravenous injection (IV) once every 6 days.
具体实施方式detailed description
术语定义： Definition of terms :
除非本文中另外指出，本文所用术语具有在其所属领域的常规含义。Unless otherwise indicated herein, terms used herein have their ordinary meanings in the art.
术语“PI3K抑制剂”在本文中是指磷脂酰肌醇3-激酶，是一类高度保守的酶家族，是胞内PI3K-Akt-mTOR信号轴的重要组成部分。PI3K抑制剂的实例包括但不限于PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。具体的实施例包括但不 限于Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003和其任意组合。优选的实例包括但不限于如本文所教导的式I化合物(本文中又称AN2025)The term "PI3K inhibitor" herein refers to phosphatidylinositol 3-kinase, which is a highly conserved enzyme family and an important part of the intracellular PI3K-Akt-mTOR signaling axis. Examples of PI3K inhibitors include, but are not limited to, inhibitors of PI3K alpha, PI3K beta, PI3K gamma, PI3K delta subtypes. Specific examples include, but are not limited to, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib, Bimiralisib, GDC-0084, ACP- 319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof. Preferred examples include, but are not limited to, compounds of formula I as taught herein (also referred to herein as AN2025)
Figure PCTCN2022104040-appb-000004
Figure PCTCN2022104040-appb-000004
术语“溶瘤病毒”在本文中指能够在肿瘤细胞中复制并能够杀死肿瘤细胞的病毒。包括呼肠病毒(reovirus)，新城疫病毒(Newcastle disease virus)，水泡性口炎病毒(vesicular stomatitis virus)，腺病毒(adenovirus)，痘苗病毒(vaccinia virus)，滤过性病毒(parapox orf virus)，辛德比斯病毒(Sindbis virus)和单纯疱疹病毒(herpes simplex virus)。其中所述溶瘤病毒包括但不限于下述病毒科成员的溶瘤病毒：肌尾噬菌体科(myoviridae)、长尾噬菌体科(siphoviridae)、短尾噬菌体科(podpviridae)、复层噬菌体科(teciviridae)、覆盖噬菌体科(corticoviridae)、芽生噬菌体科(plasmaviridae)、脂毛噬菌体科(lipothrixviridae)、微小纺锤形噬菌体科(fuselloviridae)、痘病毒科(poxyiridae)、虹彩病毒科(iridoviridae)、藻类DNA病毒科(phycodnaviridae)、杆状病毒科(baculoviridae)、疱疹病毒科(herpesviridae)、腺病毒科(adnoviridae)、乳多空病毒科(papovaviridae)、多分体DNA病毒科(polydnaviridae)、丝状噬菌体科(inoviridae)、微小噬菌体科(microviridae)、双生病毒科(geminiviridae)、圆环病毒科(circoviridae)、细小病毒科(parvoviridae)、嗜肝DNA病毒科(hepadnaviridae)、逆转录病毒科(retroviridae)、囊状噬菌体科(cyctoviridae)、呼肠孤病毒科(reoviridae)、双RNA病毒科(birnaviridae)、副粘液病毒科(paramyxoviridae)、弹状病毒科(rhabdoviridae)、丝状病毒科(filoviridae)、正粘液病毒科(orthomyxoviridae)、布尼安病毒科(bunyaviridae)、沙粒病毒科(arenaviridae)、光滑噬菌体科(leviviridae)、小RNA病毒科(picornaviridae)、伴生 病毒科(sequiviridae)、豇豆花叶病毒科(comoviridae)、马铃薯Y病毒科(potyviridae)、杯状病毒科(caliciviridae)、星状病毒科(astroviridae)、野田病毒科(nodaviridae)、四病毒科(tetraviridae)、番茄丛矮病毒科(tombusviridae)、冠状病毒科(coronaviridae)、黄病毒科(glaviviridae)、披膜病毒科(togaviridae)和杆状RNA病毒科(barnaviridae)。除此之外，提供的方法还包括免疫保护病毒以及这些病毒的重组病毒。除此之外，提供的方法还包括至少两种溶瘤病毒的联合使用。优选地，本方法提供的溶瘤病毒为呼肠病毒(reovirus)。更为优选地，本方法提供的溶瘤病毒为血清3型脱毒呼肠病毒(serotype-3dearing strain)。溶瘤病毒的实例包括但不限于Onyx-015、DNX-2401、ColoAdl、Oncos102、ProstAtak、CG0070、Pexavec、GLONC1、HF10、HSV1716、Reolysin和Cavatak。The term "oncolytic virus" herein refers to a virus capable of replicating in tumor cells and capable of killing tumor cells. Includes reovirus, Newcastle disease virus, vesicular stomatitis virus, adenovirus, vaccinia virus, parapox orf virus , Sindbis virus and herpes simplex virus. Wherein the oncolytic virus includes, but is not limited to, oncolytic viruses of members of the following virus families: myoviridae, siphoviridae, podpviridae, teciviridae ), covering corticoviridae, plasmaviridae, lipothrixviridae, fuselloviridae, poxyiridae, iridoviridae, algal DNA viruses phycodnaviridae, baculoviridae, herpesviridae, adenoviridae, papovaviridae, polydnaviridae, filamentous phages ( inoviridae, microviridae, geminiviridae, circoviridae, parvoviridae, hepadnaviridae, retroviridae, cyst Cyctoviridae, Reoviridae, Birnaviridae, Paramyxoviridae, Rhabdoviridae, Filoviridae, Orthomyxoviridae Orthomyxoviridae, Bunyaviridae, Arenaviridae, Leviviridae, Picornaviridae, Sequiviridae, Comoviridae (comoviridae), potyviridae, caliciviridae, astroviridae, nodaviridae, tetraviridae, tombusviridae , coronaviridae, glaviviridae, togaviridae and barnaviridae ae). In addition, methods are provided that include immunization against viruses and recombinant viruses of these viruses. In addition, the provided methods also include the combined use of at least two oncolytic viruses. Preferably, the oncolytic virus provided by the method is reovirus. More preferably, the oncolytic virus provided by the method is serotype-3 dearing strain. Examples of oncolytic viruses include, but are not limited to, Onyx-015, DNX-2401, ColoAdl, Oncos102, ProstAtak, CG0070, Pexavec, GLONC1, HF10, HSV1716, Reolysin, and Cavatak.
术语“PD-1抑制剂”是指“抗PD1/PDL1抗体”，其是针对程序性死亡蛋白1(PD-1)/程序性死亡蛋白配体1(PD-L1)的抗体。示例性抗体包括但不限于如专利号US7,029,674、US7,488,802、US7,521,051、US8,008,449、US8,354,509、US8,617,546和US8,709,417中所示的抗体。PD-1/PD-L1抑制剂的具体实例还包括Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗和其任意组合物。The term "PD-1 inhibitor" refers to "anti-PD1/PDL1 antibody", which is an antibody against programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1). Exemplary antibodies include, but are not limited to, those shown in Patent Nos. US7,029,674, US7,488,802, US7,521,051, US8,008,449, US8,354,509, US8,617,546, and US8,709,417. Specific examples of PD-1/PD-L1 inhibitors also include Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab Monoclonal antibody and any combination thereof.
“治疗”、“处理”和“医治”是指在有需要的对象中减轻、抑制和/或逆转疾病(如肿瘤/癌症)的发展。术语“治疗”包括疾病的成功治疗或改善的任何迹象，包括任何客观或主观参数，例如减轻；缓和；症状减少或使受试对象更容易容忍损伤、病理或病症；延迟或减缓发展速率等。治疗或改善的测量可基于例如所属领域已知的身体检查、病理学检查和/或诊断检查的结果。例如，在一个实施方案中，本发明所涉及的“治疗”癌症是指对癌症或被诊断患有癌症的对象使用本发明的PI3K抑制剂、溶瘤病毒与PD-1抑制剂联合治疗，以实现至少一项阳性治疗结果，例如癌细胞数量减少、肿瘤大小减小、肿瘤细胞浸润外周器官的速率减少或肿瘤转移或肿瘤生长速率减小。"Treating", "treating" and "treating" refer to alleviating, inhibiting and/or reversing the progression of a disease (eg, tumor/cancer) in a subject in need thereof. The term "treatment" includes any indication of successful treatment or amelioration of a disease, including any objective or subjective parameter, such as alleviation; palliation; reduction of symptoms or making the injury, pathology or condition more tolerant to the subject; delay or slowing of the rate of progression, and the like. Measures of treatment or improvement may be based, for example, on the results of physical, pathological, and/or diagnostic tests known in the art. For example, in one embodiment, the "treatment" of cancer referred to in the present invention refers to the combined treatment of PI3K inhibitors, oncolytic viruses and PD-1 inhibitors of the present invention on cancer or a subject diagnosed with cancer, to At least one positive therapeutic outcome is achieved, such as a decrease in the number of cancer cells, a decrease in tumor size, a decrease in the rate at which tumor cells infiltrate peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth.
治疗也可指与在不采取该措施的情况下将会发生的相比，减少疾病的发病或发作风险，或减少疾病复发(例如延长复发时间)。在医学领域，这种治疗也被称为“预防”。Treating can also refer to reducing the onset or risk of onset of a disease, or reducing recurrence of a disease (eg, prolonging the time to recurrence) compared to what would occur if the measure were not taken. In the medical field, this treatment is also known as "prophylaxis".
术语“有效量”或“治疗有效量”是指如通过临床测试和评估、患者观察等所记录的，可有效治疗疾病的量。“有效量”可进一步表示引起生物或化学活性的可检测到的变化的量。可检测到的变化可以由熟悉相关机制或方法的所属领域技术人员检测和/或进一步定量。此外，“有效量”可表示维持期望生理状态(即减少或预防显著的衰退和/或促进病症的改善)的量。“有效量”可进一步指治疗有效量。The term "effective amount" or "therapeutically effective amount" refers to an amount effective to treat a disease, as documented by clinical testing and evaluation, patient observation, and the like. An "effective amount" can further mean an amount that causes a detectable change in biological or chemical activity. A detectable change can be detected and/or further quantified by one skilled in the art familiar with the relevant mechanism or method. Additionally, an "effective amount" can mean an amount that maintains a desired physiological state (ie, reduces or prevents significant decline and/or promotes amelioration of a condition). An "effective amount" can further refer to a therapeutically effective amount.
在一些实施方案中，PI3K抑制剂以有效量施予对象。有效量通常是每天0.01mg/kg体重至500mg/kg体重。在一些实施方案中，药学上可接受的组合物可经过配制，使得可以向接受这些组合物的对象施用每天0.01mg/kg体重至200mg/kg体重或0.01mg/kg体重至100mg/kg体重的化合物的剂量(例如基于75kg的人，剂量为0.75mg至7.5g或15g)。在某些实施方案中，本发明的活性药物成分经过配制，以提供0.01mg/kg至70mg/kg的剂量(例如基于75kg的人，剂量为0.75mg至5.25g)。In some embodiments, the PI3K inhibitor is administered to a subject in an effective amount. An effective amount is usually 0.01 mg/kg to 500 mg/kg body weight per day. In some embodiments, the pharmaceutically acceptable compositions can be formulated so that 0.01 mg/kg body weight to 200 mg/kg body weight or 0.01 mg/kg body weight to 100 mg/kg body weight can be administered to subjects receiving these compositions. Dosage of the compound (for example a dose of 0.75 mg to 7.5 g or 15 g based on a 75 kg human). In certain embodiments, the active pharmaceutical ingredient of the invention is formulated to provide a dose of 0.01 mg/kg to 70 mg/kg (eg, a dose of 0.75 mg to 5.25 g based on a 75 kg human).
在一些实施方案中，PI3K抑制剂的有效剂量为约0.5至约250mg/kg、约1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg。在一些实施方案中，有效剂量包括约0.5mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、8mg/kg、10mg/kg、20mg/kg、25mg/kg、40mg/kg、50mg/kg、60mg/kg、75mg/kg、100mg/kg、120mg/kg、150mg/kg、175mg/kg、200mg/kg、225mg/kg、250mg/kg和300mg/kg。剂型可以采取各种合适的形式，例如片剂或胶囊，并且有效剂量可以在一个或多个单位剂型(如片剂、胶囊)中提供，并且每天提供1、2或3次，或以例如4、8或12小时的时间间隔全天提供。片剂或胶囊例如可以含有例如10、25、50、75、100、150、200、250、300、350、400、450、500、600、700、800、900、1,000、1,100或1,250mg的化合物。举例来说，在一些实施方案中将PI3K抑制剂施予人类对象可以包括在100-1,250、150-1,000、200-800或250-750mg范围的PI3K抑制剂的每日剂量，所述每日剂量可以每天一次全部施用，或者分多份以一定的时间间隔全天施用。也可以制备成液体制剂，使得可以容易地且便利地分配任何剂量。In some embodiments, the effective dosage of PI3K inhibitor is about 0.5 to about 250 mg/kg, about 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg /kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg. In some embodiments, effective doses include about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg, 20 mg/kg , 25mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 75mg/kg, 100mg/kg, 120mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg and 300mg /kg. The dosage form may take various suitable forms, such as tablets or capsules, and the effective dose may be presented in one or more unit dosage forms (such as tablets, capsules) and provided 1, 2 or 3 times a day, or in doses such as 4 , 8 or 12 hour intervals are available throughout the day. Tablets or capsules may contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100 or 1,250 mg of the compound . For example, in some embodiments, administering a PI3K inhibitor to a human subject can include a daily dose of the PI3K inhibitor in the range of 100-1,250, 150-1,000, 200-800, or 250-750 mg, the daily dose being It can be administered once a day in its entirety, or in multiple portions at regular intervals throughout the day. Liquid preparations can also be prepared to allow easy and convenient dispensing of any dosage.
在一些实施方案中，溶瘤病毒以有效剂量施予对象。有效剂量根据个体差异来决定，其影响因素包括但不限于年龄，性别，体重以及肿瘤的特性，比如肿瘤的类型和大小等。对于施予对象来说，有效剂量通常是10 3-10 12PFU或者TCID 50。有效剂量也可以是1.0PFU/kg体重至约10 15PFU/kg体重，例如从10 2PFU/kg体重至10 13PFU/kg体重。优选的，有效剂量是约1×10 8至1×10 12PFU或者TCID 50。例如，对于施予对象，有效剂量为约10 2至10 17PFU。 In some embodiments, an oncolytic virus is administered to a subject in an effective dose. The effective dose is determined according to individual differences, and its influencing factors include but not limited to age, sex, body weight and characteristics of the tumor, such as the type and size of the tumor. An effective dose is generally 10 3 -10 12 PFU or TCID 50 for administration to a subject. An effective dose may also be from 1.0 PFU/kg body weight to about 10 15 PFU/kg body weight, for example from 10 2 PFU/kg body weight to 10 13 PFU/kg body weight. Preferably, the effective dose is about 1×10 8 to 1×10 12 PFU or TCID 50 . For example, for administration to a subject, an effective dose is about 102 to 1017 PFU.
在一些实施方案中，溶瘤病毒可以以单次或者多次给药的方式施予对象，多次给药可以同时发生，也可以连续发生。例如，给药可以持续几天至几周。溶瘤病毒可以在同一个个体中施予一个或者多个肿瘤部位。剂型可以采取各种合适的形式，例如以经口服、***或经消化道外途径的剂型施用所述溶瘤病毒，并且有效剂量可以在一个或者多个单位剂型(例如：片剂和胶囊)中提供，并且每天至少提供一次。片剂和胶囊例如可以包含约10 2PFU至约10 17PFU剂量的溶瘤病毒。例如所述剂量为10 2、10 3、10 4、10 5、10 6、10 7、10 8、10 9、10 10、10 11、10 12、10 13、10 14、10 15、10 16、10 17PFU或者TCID 50或以上任意两个数值之间的值。抗体通常将在施用前与药学上可接受的无毒载体物质(例如生理盐水或磷酸盐缓冲盐水)混合，并且可以使用任何医学上适当的程序施用，所述医学上适当的程序例如包括但不限于静脉内或动脉内施用和注射到脑脊髓液中。在某些情况下，腹膜内、皮内、腔内、鞘内或直接施予肿瘤或为肿瘤供血的动脉可能是有利的。 In some embodiments, the oncolytic virus can be administered to the subject in a single or multiple doses, and the multiple doses can occur simultaneously or sequentially. For example, administration can last from several days to several weeks. Oncolytic viruses can be administered to one or more tumor sites in the same individual. The dosage form can take various suitable forms, such as administering the oncolytic virus in a dosage form by oral, buccal or parenteral route, and the effective dose can be in one or more unit dosage forms (such as: tablets and capsules) Provided, and provided at least once a day. Tablets and capsules, for example, may contain the oncolytic virus at a dose of about 10 2 PFU to about 10 17 PFU. For example, the dosage is 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 , 10 15 , 10 16 , 10 17 PFU or a value between any two values of TCID 50 or above. Antibodies will generally be mixed with a pharmaceutically acceptable non-toxic carrier substance (such as physiological saline or phosphate buffered saline) prior to administration, and may be administered using any medically appropriate procedure, including, for example, but not Restricted to intravenous or intraarterial administration and injection into cerebrospinal fluid. In some cases, intraperitoneal, intradermal, intracavity, intrathecal, or direct administration to the tumor or an artery supplying the tumor may be advantageous.
在一些实施方案中，抗体的有效剂量是约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg。在一些实施方案中，有效剂量包括5mg/kg、10mg/kg、20mg/kg、25mg/kg、40mg/kg、50mg/kg、60mg/kg、75mg/kg、100mg/kg、120mg/kg、150mg/kg、175mg/kg、200mg/kg、225mg/kg、250mg/kg和300mg/kg。剂型可以采取例如片剂或胶囊的形式，并且有效剂量可以在一个或多个片剂、胶囊等中提供，并且每天提供一次或以例如4、8或12小时的时间间隔全天提供。片剂或胶囊例如可以含有例如10、25、50、75、100、150、200、250、300、350、400、450、500、600、700、800、900或1,000mg抗体。也可以制备液体制剂，使得可以容易地且便利地分配任何剂量。In some embodiments, the effective dosage of the antibody is about 5 to about 250 mg/kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg. In some embodiments, effective doses include 5 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 75 mg/kg, 100 mg/kg, 120 mg/kg, 150 mg /kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg and 300mg/kg. Dosage forms may take the form of, for example, tablets or capsules, and an effective dose may be presented in one or more tablets, capsules, etc., and provided once a day or at intervals of, for example, 4, 8 or 12 hours throughout the day. A tablet or capsule may contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 mg of antibody. Liquid preparations can also be prepared to allow easy and convenient dispensing of any dosage.
在一些实施方案中，抗体以有效量施予受试对象。有效量通常是每天0.01mg/kg体重至500mg/kg体重。在一些实施方案中，药学上可接受的组合物 可经过配制，使得可以向接受这些组合物的患者施用每天0.01mg/kg体重至200mg/kg体重或0.01mg/kg体重至100mg/kg体重的化合物的剂量(例如基于75kg的人，剂量为0.75mg至7.5g或15g)。在某些实施方案中，本发明的组合物经过配制，以提供0.01mg/kg至70mg/kg的剂量(例如基于75kg的人，剂量为0.75mg至5.25g)。In some embodiments, the antibody is administered to a subject in an effective amount. An effective amount is usually 0.01 mg/kg to 500 mg/kg body weight per day. In some embodiments, the pharmaceutically acceptable compositions can be formulated so that 0.01 mg/kg body weight to 200 mg/kg body weight or 0.01 mg/kg body weight to 100 mg/kg body weight per day can be administered to patients receiving these compositions. Dosage of the compound (for example a dose of 0.75 mg to 7.5 g or 15 g based on a 75 kg human). In certain embodiments, compositions of the invention are formulated to provide a dose of 0.01 mg/kg to 70 mg/kg (eg, a dose of 0.75 mg to 5.25 g based on a 75 kg human).
抗体的有效量可以是例如每剂量0.05mg/kg、0.1mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg或8mg/kg(例如基于75kg的人，剂量为3.75mg至600mg)。An effective amount of the antibody can be, for example, 0.05 mg/kg, 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg or 8 mg/kg per dose (eg doses of 3.75 mg to 600 mg based on a 75 kg human).
抗体的剂量可以在治疗过程中每周一次、两次、三次、四次、五次或更多次、每周一次、每两周一次、或甚至每三周一次施用。给药时间可以是每天一次、每两天一次、每三天一次、每四天一次、每五天一次、每周一次、每两周一次或每三周一次。可以制备包含抗体的制剂，使得可以容易地且便利地分配任何剂量。Doses of the antibody may be administered once, twice, three, four, five or more times, weekly, every two weeks, or even every three weeks during the course of treatment. The dosing time can be once a day, once every two days, once every three days, once every four days, once every five days, once a week, once every two weeks or once every three weeks. Formulations comprising antibodies can be prepared such that any dosage can be dispensed easily and conveniently.
术语“对象”是指哺乳动物对象，并且尤其是人类对象，包括雄性或雌性对象，并且包括新生儿、婴儿、幼儿、青少年、成人或老年人对象，并且进一步包括各种人种和种族，例如高加索人种、非洲人种和亚洲人种。本文中，所述对象患有肿瘤/癌症。在一个实施方案中，不考虑所述肿瘤患者是否表达PD-L1。在另一个实施方案中，所述肿瘤患者是PD-L1表达阳性的肿瘤患者。The term "subject" refers to a mammalian subject, and especially a human subject, including male or female subjects, and including neonatal, infant, toddler, juvenile, adult or elderly subjects, and further includes various races and ethnicities, such as Caucasian, African and Asian. Herein, the subject has a tumor/cancer. In one embodiment, it is not considered whether the tumor patient expresses PD-L1. In another embodiment, the tumor patient is a tumor patient with positive expression of PD-L1.
术语“可药用盐”是指本发明式I或式II化合物的相对无毒的无机或有机酸盐。这些盐可以在化合物的最终分离和纯化期间原位制备，或者通过将游离形态的经纯化化合物分别与合适的有机酸或无机酸反应并分离如此形成的盐而制备。代表性的酸盐包括(但不限于)乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、右旋樟脑磺酸盐、柠檬酸盐、环磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖酸盐、硬脂酸盐、琥珀酸盐、丹宁酸盐、酒石酸盐、甲苯磺 酸盐、三氟乙酸盐和昔萘酸盐。在一个实施方案中，药学上可接受的盐是盐酸盐/氯化物盐。The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid salt of a compound of formula I or formula II of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by reacting the purified compound in free form with a suitable organic or inorganic acid, respectively, and isolating the salt thus formed. Representative acid salts include (but are not limited to) acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate , borate, D-camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconic acid Salt, glucuronate, hexafluorophosphate, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactic acid Salt, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotic acid Salt, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, sugar salt, stearate, succinate, tannin salt, tartrate, tosylate, trifluoroacetate and xinafoate. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride/chloride salt.
术语“肿瘤”和“癌症”在本文中可互换使用，表示机体局部组织的失控的异常增生。如果不及时进行医疗介入，肿瘤/癌症可以不受控制地生长，并有可能转移到机体其他位置，最终造成机体死亡。The terms "tumor" and "cancer" are used interchangeably herein to refer to an uncontrolled abnormal growth of a tissue in a localized area of the body. Without timely medical intervention, the tumor/cancer can grow uncontrollably and potentially metastasize to other locations in the body, eventually killing the body.
术语“癌症”可以包括由遗传继承的突变引起的癌症。此类癌症的实例包括但不限于乳腺癌、可能与李弗劳明综合征相关的癌症(例如儿童肉瘤、白血病和脑癌)、可能与林奇综合征相关的癌症例如结肠癌、胆管癌、脑癌、子宫内膜癌、肾癌、卵巢癌、胰腺癌、小肠癌、胃癌和输尿管癌、肺癌、黑素瘤、***癌、视网膜母细胞瘤、甲状腺癌和子宫癌。The term "cancer" may include cancers caused by genetically inherited mutations. Examples of such cancers include, but are not limited to, breast cancer, cancers that may be associated with Li-Frauming syndrome (such as childhood sarcoma, leukemia, and brain cancer), cancers that may be associated with Lynch syndrome such as colon cancer, bile duct cancer, Cancers of the brain, endometrium, kidney, ovary, pancreas, small intestine, stomach and ureter, lung, melanoma, prostate, retinoblastoma, thyroid and uterus.
此外，癌症可以是获得性突变(例如由饮食、环境和/或生活方式引起的突变)或体细胞突变的结果。此类癌症的实例可以包括(但不限于)肾上腺癌、肾上腺皮质癌、膀胱癌、脑癌、原发性脑癌、神经胶质瘤、胶质母细胞瘤、乳腺癌、***、结肠癌(非限制性实例包括结肠直肠癌，例如结肠腺癌和结肠腺瘤)、子宫内膜癌、上皮癌、食管癌、胆囊癌、泌尿生殖道癌、头颈癌、肾癌、肝癌、肺癌(非限制性实例包括腺癌、小细胞肺癌和非小细胞肺癌)、淋巴瘤(非限制性实例包括B细胞淋巴瘤、T细胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤)、黑素瘤、恶性黑素瘤、恶性类癌、恶性胰腺胰岛素瘤、骨髓瘤、多发性骨髓瘤、卵巢癌、胰腺癌(例如外分泌胰腺癌)、***癌、肾细胞癌、皮肤癌(除了先前提到的癌症以外，例如鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、甲状腺滤泡状癌、威尔姆氏瘤、绒毛膜癌、蕈样肉芽肿病、恶性高钙血症、颈椎增生、白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、毛细胞淋巴瘤、伯基特氏淋巴瘤、急性骨髓性白血病、慢性骨髓性白血病、骨髓增生异常综合征、早幼粒细胞性白血病、慢性粒细胞白血病、急性粒细胞白血病、纤维肉瘤、横纹肌肉瘤、星形细胞瘤、神经母细胞瘤、横纹肌肉瘤、神经鞘瘤、卡波西氏肉瘤、真性红细胞增多症、原发性血小板增多症、霍奇金氏病、非霍奇金氏淋巴瘤、软组织肉瘤、骨源性肉瘤、原发性巨球蛋白血症、***瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤和视网膜母细胞瘤。In addition, cancer can be the result of acquired mutations (such as those caused by diet, environment, and/or lifestyle) or somatic mutations. Examples of such cancers may include, but are not limited to, adrenal cancer, adrenocortical cancer, bladder cancer, brain cancer, primary brain cancer, glioma, glioblastoma, breast cancer, cervical cancer, colon cancer (non-limiting examples include colorectal cancer, such as colon adenocarcinoma and colon adenoma), endometrial cancer, epithelial cancer, esophageal cancer, gallbladder cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (non- Limiting examples include adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), lymphoma (non-limiting examples include B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma) , melanoma, malignant melanoma, malignant carcinoid, malignant pancreatic insulinoma, myeloma, multiple myeloma, ovarian cancer, pancreatic cancer (such as exocrine pancreatic cancer), prostate cancer, renal cell carcinoma, skin cancer (except Cancers other than those previously mentioned, such as squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, thyroid follicular carcinoma, Wilm's tumor, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, Cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell lymphoma, Burkitt's lymphoma, acute myeloid leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic Leukemia, chronic myeloid leukemia, acute myeloid leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, rhabdomyosarcoma, schwannoma, Kaposi's sarcoma, polycythemia vera, essential platelets Polycythemia, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, seminoma, teratoma, osteosarcoma, dry skin pigmentation keratosis, keratoacanthoma, and retinoblastoma.
“转移性癌症”是指其中来自一个器官或身体部分的癌细胞已经(通过“转移”)扩散到另一个非相邻器官或身体部分的癌症。非相邻器官或身体部分处的癌症(“继发性肿瘤”或“转移性肿瘤”)包括来源于癌症或癌细胞已经从该器官或身体部分扩散的器官或身体部分的癌细胞。可以发生继发性肿瘤的部位包括(但不限于)***、肺、肝、脑和/或骨头。"Metastatic cancer" is cancer in which cancer cells from one organ or body part have spread (by "metastasis") to another non-adjacent organ or body part. Cancer at a non-adjacent organ or body part ("secondary tumor" or "metastatic tumor") includes cancer cells originating from an organ or body part where the cancer or cancer cells have spread from that organ or body part. Sites where secondary tumors can occur include, but are not limited to, lymph nodes, lung, liver, brain, and/or bone.
本文中，术语“可药用”和“药学上可接受”可互换使用，是指制药领域技术人员一般接受的类型。例如可药用盐、可药用载体等。Herein, the terms "pharmaceutically acceptable" and "pharmaceutically acceptable" are used interchangeably to refer to the type generally accepted by those skilled in the pharmaceutical arts. For example, pharmaceutically acceptable salts, pharmaceutically acceptable carriers and the like.
“口服剂型”是指经制备用于通过口服施用途径用于个体的药物制剂。已知的口服剂型的实例包括但不限于片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂等。在一些方法，粉末、丸剂、颗粒、胶囊和片剂可经适宜聚合物或常用包衣材料包被以达到(例如)在胃肠中的更高稳定性或达到期望释放速率。此外，粉末、丸剂或颗粒的胶囊壳经进一步包被。片剂可以刻痕以促进给药分割。"Oral dosage form" refers to a pharmaceutical formulation prepared for use in an individual by the oral route of administration. Examples of known oral dosage forms include, but are not limited to, tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, and the like. In some methods, powders, pills, granules, capsules and tablets can be coated with suitable polymers or commonly used coating materials to achieve, for example, greater stability in the gastrointestinal tract or to achieve a desired rate of release. In addition, the capsule shells of powders, pills or granules are further coated. Tablets may be scored to facilitate dosing division.
本发明所述的式I化合物作为口服制剂施用时，其优选地被膜包被。适宜膜为本领域已知且可自市场购得或可根据已知方法来制造。通常，膜衣材料是亲水聚合物，例如聚乙二醇、聚乙烯吡咯啶酮、聚乙烯醇、羟丙基纤维素、羟甲基纤维素和羟丙基甲基纤维素等。膜衣组合物成份可包括常用量的增塑剂，例如聚乙二醇、柠檬酸三乙酯、邻苯二甲酸二乙酯、丙二醇、甘油；以及遮光剂，例如二氧化钛和着色剂，例如氧化铁，铝色淀等。通常，膜衣材料是以例如可提供介于固体口服剂剂型的1％至6％范围内的膜衣的量来施加。When the compounds of formula I according to the invention are administered as oral formulations, they are preferably film-coated. Suitable membranes are known in the art and are commercially available or can be manufactured according to known methods. Typically, the film coating material is a hydrophilic polymer such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose, among others. The film coating composition ingredients may include plasticizers such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, glycerin in usual amounts; and opacifiers such as titanium dioxide and colorants such as oxidized Iron, aluminum lakes, etc. Typically, the film coating material is applied in such an amount as to provide a film coating in the range of 1% to 6% of the solid oral dosage form, for example.
本发明溶瘤病毒作为静脉滴注制剂施用时，可以选择如下两种常用的流体：晶体流体和胶体流体。晶体是矿物盐或其他水溶性分子的水溶液。胶体含有较大的不溶性分子，如明胶；血液本身是胶体。最常用的晶体流体为生理盐水，即0.9％的氯化钠溶液，其接近血液中的浓度(等渗)。林格乳酸或林格醋酸是另一种等渗溶液，常用于大体积流体置换。其他药学上可接受的载体包括磷酸盐缓冲盐水或其他生理上可接受的缓冲液、乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、树胶粉、磷酸钙、藻酸盐、黄芩、明胶、硅酸钙、微晶、纤维素、聚乙烯吡咯烷酮、纤维素、无菌水、糖浆和甲基纤维素。药物组合物还可包括但不限于润 滑剂，例如滑石粉、硬脂酸镁和矿物油；润湿剂；乳化剂和悬浮剂；防腐剂，如羟基苯甲酸甲酯和丙酯；甜味剂；以及调味剂。When the oncolytic virus of the present invention is administered as an intravenous drip preparation, the following two commonly used fluids can be selected: crystal fluid and colloid fluid. Crystals are aqueous solutions of mineral salts or other water-soluble molecules. Colloids contain larger insoluble molecules such as gelatin; blood itself is a colloid. The most commonly used crystalloid fluid is physiological saline, a 0.9% solution of sodium chloride, which is close to the concentration in blood (isotonic). Ringer's lactic acid or Ringer's acetic acid is another isotonic solution commonly used for large volume fluid replacement. Other pharmaceutically acceptable carriers include phosphate buffered saline or other physiologically acceptable buffers, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum powder, calcium phosphate, alginate, baicalin, gelatin , Calcium Silicate, Microcrystalline, Cellulose, Polyvinylpyrrolidone, Cellulose, Sterile Water, Syrup and Methylcellulose. The pharmaceutical composition may also include, but is not limited to, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylparabens; sweetening agents ; and flavoring agents.
除非另有说明，否则如本文所用术语“包含”和“包括”具有开放性和非限制性含义。例如，除本发明的PI3K抑制剂、溶瘤病毒与PD-1抑制剂所形成的药物组合之外，还可以包含其它治疗剂，例如“生物治疗剂”、“化学治疗剂”。Unless otherwise stated, the terms "comprises" and "including" as used herein have an open and non-limiting meaning. For example, in addition to the drug combination formed by the PI3K inhibitor, oncolytic virus and PD-1 inhibitor of the present invention, other therapeutic agents such as "biotherapeutic agents" and "chemotherapeutic agents" may also be included.
其中，“生物治疗剂”是指生物分子，例如抗体或融合蛋白，其在支持肿瘤维持和/或生长或抑制肿瘤免疫应答的任何生物通路中阻断配体/受体性。例如“生物治疗剂”包括但不限于：阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、纳武利尤单抗、阿替珠单抗、度伐单抗、阿维单抗。Herein, "biotherapeutic agent" refers to a biomolecule, such as an antibody or a fusion protein, that blocks ligand/receptor activity in any biological pathway that supports tumor maintenance and/or growth or suppresses tumor immune responses. For example, "biotherapeutic agents" include, but are not limited to: alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab monoclonal antibody, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, nivolumab, a Ticilizumab, Durvalumab, Avelumab.
其中，“化学治疗剂”是可以用于癌症治疗的化学化合物，包括但不限于烷化剂、抗代谢物、激酶抑制剂、纺锤体毒素植物生物碱、细胞毒性/抗肿瘤生物素、拓扑异构酶抑制剂、光敏剂、抗***和选择性***受体调节剂、芳香酶抑制剂、EGFR抑制剂、VEGF抑制剂、抑制与细胞增殖异常或肿瘤生长有关的基因表达的反义寡核苷酸。例如，化学治疗剂的实例包括但不限于苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、***、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、 鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib。Among them, "chemotherapeutic agents" are chemical compounds that can be used in cancer treatment, including but not limited to alkylating agents, antimetabolites, kinase inhibitors, spindle toxin plant alkaloids, cytotoxic/antitumor biotin, topoiso Constructase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, antisense oligos that inhibit the expression of genes associated with abnormal cell proliferation or tumor growth Nucleotides. For example, examples of chemotherapeutic agents include, but are not limited to, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, Cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, Vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone , bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, Thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, boron Tezomib, bosutinib, britinib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danucetib, dasatinib, multidimensional Tini, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib , motisanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib , Saracatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, Verofini, Vimodeji, volasertib.
对于本发明的联合治疗的剂量方案的选择取决于多个因素，例如：受治疗的个体的实体血清或组织翻转率、症状水平、整体免疫原性和靶细胞、组织或器官的可接近程度。优选地，剂量方案将递送至患者的每种治疗剂的量最大化，符合可接受的副作用水平。因此，联合治疗中每种生物治疗剂和化学治疗剂的剂量和给药频率部分取决于具体的治疗剂、受治疗的癌症的严重程度和患者的表征。The choice of dosage regimen for the combination therapy of the invention will depend on factors such as: the rate of substantial serum or tissue turnover, the level of symptoms, the overall immunogenicity and the accessibility of the target cells, tissues or organs in the individual being treated. Preferably, the dosage regimen maximizes the amount of each therapeutic agent delivered to the patient, consistent with acceptable levels of side effects. Thus, the dosage and frequency of administration of each biotherapeutic and chemotherapeutic agent in the combination therapy will depend in part on the particular therapeutic agent, the severity of the cancer being treated and the characteristics of the patient.
本发明的联合治疗可以在移除肿瘤的手术前或后施用，也可以在放射治疗之前、期间、或之后施用。The combination therapy of the invention may be administered before or after surgery to remove the tumor, and may be administered before, during, or after radiation therapy.
WO2007084786具体阐述了本发明的式I化合物，该化合物或其药学上可接受的盐和其制备工艺公开于WO2007084786的实施例中，其以全文引用方式并入本文中。WO2007084786 specifically describes the compound of formula I of the present invention, the compound or its pharmaceutically acceptable salt and its preparation process are disclosed in the examples of WO2007084786, which is incorporated herein by reference in its entirety.
以下通过实施例来进一步阐述本发明，但实施例不意味着对本发明的保护范围做任何限定。The present invention is further illustrated by the following examples, but the examples are not meant to limit the protection scope of the present invention in any way.
在一些实施方案中，PI3K抑制剂、溶瘤病毒与PD-1抑制剂组合施用导致所述PD-1抑制剂增强，使得例如更小剂量或者更长时间间隔的PD-1抑制剂对于治疗可能是有效的。In some embodiments, administration of a PI3K inhibitor, an oncolytic virus in combination with a PD-1 inhibitor results in potentiation of the PD-1 inhibitor, making, for example, smaller doses or longer intervals of PD-1 inhibitor therapy possible. It's effective.
“抗体”包括所有类型的免疫球蛋白，包括IgG、IgM、IgA、IgD和IgE或其片段，其可适用于本文所公开的医学用途。抗体可以是单克隆的或多克隆的，并且可以属于任何物种来源，包括例如小鼠、大鼠、兔、马或人。与本发明中使用的抗体所结合的蛋白质或表位(PDL1或PD1)保持特异性结合的抗体片段包括在术语“抗体”的范围内。此类片段可以通过已知技术产生。抗体可以是嵌合的或人源化的，尤其当其用于治疗目的时。抗体可以使用所属领域中已知的方法获得或制备。"Antibody" includes immunoglobulins of all classes, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, which may be suitable for the medical uses disclosed herein. Antibodies may be monoclonal or polyclonal and may be of any species origin including, for example, mouse, rat, rabbit, horse or human. Antibody fragments that retain specific binding to the protein or epitope (PDL1 or PD1) to which the antibody used in the present invention binds are included within the scope of the term "antibody". Such fragments can be produced by known techniques. Antibodies can be chimeric or humanized, especially when they are used for therapeutic purposes. Antibodies can be obtained or prepared using methods known in the art.
为了可以更充分地理解本文中描述的发明，列出以下实施例。应理解这些实施例仅用于说明性目的，而不应解释为以任何方式限制本发明。So that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.
具体实施例specific embodiment
实施例1：式I化合物(AN2025)、溶瘤病毒(Pelareorep)与抗PD-1抗体的组合疗法治疗小鼠EMT6肿瘤Embodiment 1: The combination therapy of formula I compound (AN2025), oncolytic virus (Pelareorep) and anti-PD-1 antibody treats mouse EMT6 tumor
材料和方法Materials and methods
试剂和仪器：Pelareorep由本公司提供；AN2025购买自MedChem Express。针对小鼠的PD-1的抗体(克隆号：RMP1-14)购买自BioXcell。Reagents and instruments: Pelareorep was provided by our company; AN2025 was purchased from MedChem Express. Antibody against mouse PD-1 (clone number: RMP1-14) was purchased from BioXcell.
细胞系：小鼠乳腺癌EMT6细胞(CRL-2755)购自美国组织培养中心。细胞在补充有10％胎牛血清的DMEM培养基中，在培养箱中以37℃和5％二氧化碳条件培养，并每周传代培养两次，直至获得必需数量的用于接种小鼠的细胞。Cell line: mouse breast cancer EMT6 cells (CRL-2755) were purchased from American Tissue Culture Center. Cells were cultured in DMEM medium supplemented with 10% fetal bovine serum in an incubator at 37°C and 5% carbon dioxide, and subcultured twice a week until the necessary number of cells for inoculating mice was obtained.
动物：6-8周的BalB/c雌性小鼠购自The Jackson Laboratory。动物被圈养在微型隔离笼中，执行12h光/暗循环。笼每周更换两次。每周观察一次动物并记录临床征象。Animals: 6-8 week old BalB/c female mice were purchased from The Jackson Laboratory. Animals were housed in microisolator cages on a 12h light/dark cycle. Cages were changed twice a week. Animals were observed weekly and clinical signs were recorded.
动物研究：收获体外培养的EMT6细胞，以2×10 6细胞/ml的细胞浓度悬浮于100μl无血清培养基中，并使用注射器在右侧下方背部皮下(sc)注入小鼠。在细胞植入若干天后，基于肿瘤大小随机分配小鼠，使得每组小鼠的肿瘤平均体积为76.82mm 3。AN2025给药：30mg/kg，每天口服(PO)一次。Pelareorep给药：2×10 8TCID 50连续2天每天静脉给药一次，然后停药4天，以此作为一个给药周期进行后续给药。抗PD-1抗体给药：10mg/kg，以每6天静脉注射(IV)一次的方式进行给药。用数显卡尺每周2-3次测量肿瘤大小，并使用公式(l×w 2)/2＝mm 3计算体积，其中l和w是指在每次测量中收集的较大和较小正交尺寸。使用GraphPad Prism 9软件绘制群组肿瘤大小(平均±SEM)对比时间的曲线图。使用Repeated measure(RM)two-way ANOVA检验进行分析进行统计分析。 Animal study: EMT6 cells cultured in vitro were harvested, suspended in 100 μl serum-free medium at a cell concentration of 2×10 6 cells/ml, and injected into mice subcutaneously (sc) on the right lower back using a syringe. Several days after cell implantation, mice were randomly assigned based on tumor size such that the average tumor volume of each group of mice was 76.82 mm 3 . AN2025 administration: 30mg/kg, orally (PO) once a day. Pelareorep administration: 2×10 8 TCID 50 was given intravenously once a day for 2 consecutive days, and then the medicine was stopped for 4 days, which was used as a dosing cycle for subsequent dosing. Anti-PD-1 antibody administration: 10mg/kg, administered intravenously (IV) once every 6 days. Measure the tumor size 2-3 times a week with digital calipers and calculate the volume using the formula (l×w 2 )/2=mm 3 , where l and w refer to the larger and smaller orthogonals collected at each measurement size. Cohort tumor size (mean ± SEM) was plotted versus time using GraphPad Prism 9 software. Statistical analysis was performed using Repeated measure (RM) two-way ANOVA test for analysis.
实验结果Experimental results
如图1所示，尽管Pelareorep、抗PD-1抗体、AN2025任意两两组合在小鼠乳腺癌EMT6模型上都体现出了一定的抗肿瘤活性。但是Pelareorep、抗PD-1抗体和AN2025三者联用所带来的抗肿瘤活性要优于任意两两组合，并显著优于AN2025与抗PD-1抗体联用活性(G5Vs G3,p<0.05)。As shown in Figure 1, although any pairwise combination of Pelareorep, anti-PD-1 antibody, and AN2025 showed certain anti-tumor activity in the mouse breast cancer EMT6 model. However, the anti-tumor activity brought about by the combination of Pelareorep, anti-PD-1 antibody and AN2025 was better than any pairwise combination, and was significantly better than the activity of the combination of AN2025 and anti-PD-1 antibody (G5Vs G3, p<0.05 ).

Claims (37)

  1. 一种在有此需要的对象中***/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的方法，包括向所述对象施用PI3K抑制剂、溶瘤病毒以及PD-1抑制剂，其中，所述PI3K抑制剂、溶瘤病毒和PD-1抑制剂可以同时、分开或者顺序施用。A method of treating tumor/cancer and/or generating a memory immune response against tumor/cancer in a subject in need thereof, comprising administering to said subject a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, wherein, The PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be administered simultaneously, separately or sequentially.
  2. 如权利要求1所述的方法，其中所述PI3K抑制剂选自PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。The method of claim 1, wherein the PI3K inhibitor is selected from the group consisting of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ subtype inhibitors.
  3. 如权利要求1或2所述的方法，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003和其任意组合。The method according to claim 1 or 2, wherein the PI3K inhibitor is selected from Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604 , Acalisib, Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003 and any combination thereof .
  4. 如权利要求1-3任意一项所述的方法，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，The method according to any one of claims 1-3, wherein the PI3K inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022104040-appb-100001
    Figure PCTCN2022104040-appb-100001
  5. 如权利要求1-4任意一项所述的方法，其中所述溶瘤病毒包括天然存在的、经过修饰的或经过重组的具有复制能力，并且能够侵染和裂解肿瘤细胞的病毒。The method according to any one of claims 1-4, wherein the oncolytic virus includes a naturally occurring, modified or recombinant virus capable of replicating and capable of infecting and lysing tumor cells.
  6. 如权利要求1-5任意一项所述的方法，其中溶瘤病毒选自呼肠病毒(reovirus)，新城疫病毒(Newcastle disease virus)，水泡性口炎病毒(vesicular stomatitis virus)，腺病毒(adenovirus)，痘苗病毒(vaccinia virus)，滤过性病毒(parapox orf virus)，辛德比斯病毒(Sindbis virus)和单纯疱疹病毒(herpes simplex virus)。The method according to any one of claims 1-5, wherein the oncolytic virus is selected from reovirus (reovirus), Newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus ( adenovirus), vaccinia virus, parapox orf virus, Sindbis virus and herpes simplex virus.
  7. 如权利要求1-6任意一项所述的方法，其中所述PD-1抑制剂选自：抗PD-1抗体、抗PD-L1抗体和抗PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗和其任意组合物。The method according to any one of claims 1-6, wherein the PD-1 inhibitor is selected from: anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody; preferably, wherein the PD The -1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimab, Sintilimumab, Tislelizumab, Camrelizumab, and any combination thereof.
  8. 如权利要求1-7任意一项所述的方法，其中以经口服、***或经消化道外途径的剂型施用所述PI3K抑制剂，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。The method according to any one of claims 1-7, wherein the PI3K inhibitor is administered orally, orally or in a dosage form outside the digestive tract, for example, the dosage form of the oral route can be tablet, capsule, powder , pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example, dosage forms for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal , Intratumoral, transdermal, transmucosal drug delivery.
  9. 如权利要求1-8任意一项所述的方法，其中每天施用所述PI3K抑制剂1次或2次；或者每2、3、4、5、6、7、8、9或10天或每1、2或3周施用1次所述PI3K抑制剂；或者每周连续1、2、3、4、5或6天每天施用1次所述PI3K抑制剂，然后间隔6、5、4、3、2或1天。The method according to any one of claims 1-8, wherein the PI3K inhibitor is administered once or twice a day; or every 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or every The PI3K inhibitor was administered once in 1, 2, or 3 weeks; or the PI3K inhibitor was administered once a day for 1, 2, 3, 4, 5, or 6 consecutive days a week, and then at intervals of 6, 5, 4, 3 , 2 or 1 day.
  10. 如权利要求1-9任意一项所述的方法，其中所述PI3K抑制剂在成年人中以约20mg/天-约200mg/天、约30mg/天-约160mg/天、约60mg/天-约120mg/天的剂量范围施用。The method according to any one of claims 1-9, wherein the PI3K inhibitor is administered in an adult at about 20 mg/day to about 200 mg/day, about 30 mg/day to about 160 mg/day, about 60 mg/day to A dosage range of about 120 mg/day is administered.
  11. 如权利要求1-10任意一项所述的方法，其中以约0.5至约250mg/kg、约1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg或约20至约120mg/kg的有效剂量向所述对象施用所述PI3K抑制剂。The method according to any one of claims 1-10, wherein about 0.5 to about 250 mg/kg, about 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 The PI3K inhibitor is administered to the subject at an effective dose of up to about 250 mg/kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg.
  12. 如权利要求1-11任意一项所述的方法，其中以经口服、***或经消化道外途径的剂型施用所述溶瘤病毒，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。The method according to any one of claims 1-11, wherein the oncolytic virus is administered orally, buccally or in a dosage form outside the digestive tract, for example, the dosage form of the oral route can be tablets, capsules, powders , pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example, dosage forms for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal , Intratumoral, transdermal, transmucosal drug delivery.
  13. 如权利要求1-12任意一项所述的方法，其中每天施用溶瘤病毒至少一次，在第2、3、4、5、6、7、8、9、10、14、21或28天里重复给药，或者任何2-28天时间内，或者更长时间，每天连续或者间断的施用溶瘤病毒1、2、3、4、5、 6、7、8、9、10、12或24小时或者1-24小时中的任何时间；优选地，给药持续时间为5、15、30、60、90、120、150或180分钟或者5-180分钟的任何时间或者更长时间。The method of any one of claims 1-12, wherein the oncolytic virus is administered at least once a day, on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21 or 28 Repeated administration, or any period of 2-28 days, or longer, daily continuous or intermittent administration of oncolytic virus 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 24 hours or any time from 1 to 24 hours; preferably, the duration of administration is 5, 15, 30, 60, 90, 120, 150 or 180 minutes or any time from 5 to 180 minutes or longer.
  14. 如权利要求1-13任意一项所述的方法，其中所述溶瘤病毒在成年人中的施用剂量根据个体差异(年龄，体重，性别)，施用病毒的不同而不同，例如以每人约10 2-10 17PFU(菌落形成单位)或者TCID 50(半数组织培养感染剂量)施用。 The method according to any one of claims 1-13, wherein the dosage of the oncolytic virus in adults is different according to individual differences (age, body weight, sex), and different viruses, such as about 10 2 -10 17 PFU (colony forming units) or TCID 50 (half the tissue culture infectious dose) were administered.
  15. 如权利要求1-14任意一项所述的方法，其中以约1.0PFU/kg至约10 15PFU/kg的有效剂量向所述对象施用所述溶瘤病毒。 The method of any one of claims 1-14, wherein the oncolytic virus is administered to the subject at an effective dose of about 1.0 PFU/kg to about 1015 PFU/kg.
  16. 如权利要求1-15任意一项所述的方法，其中以消化道外途径施用所述PD-1抑制剂，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药。The method according to any one of claims 1-15, wherein the PD-1 inhibitor is administered by an extradigestive route, for example, the extradigestive route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, cranial Intradermal, intrathecal, intratumoral, transdermal, transmucosal administration.
  17. 如权利要求1-16任意一项所述的方法，其中所述PD-1抑制剂配制成溶液剂、冻干剂、粉针剂。The method according to any one of claims 1-16, wherein the PD-1 inhibitor is prepared as a solution, a lyophilized preparation, or a powder injection.
  18. 如权利要求1-17任意一项所述的方法，其中以0.05mg/kg、0.1mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg或8mg/kg的有效剂量施用所述PD-1抑制剂。The method according to any one of claims 1-17, wherein 0.05mg/kg, 0.1mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, The PD-1 inhibitor is administered at an effective dose of 7 mg/kg or 8 mg/kg.
  19. 如权利要求1-18任意一项所述的方法，其中所述肿瘤/癌症包括原发肿瘤/癌症，复发肿瘤/癌症或转移性肿瘤/癌症，包括实体瘤和血液瘤。The method according to any one of claims 1-18, wherein said tumor/cancer comprises primary tumor/cancer, recurrent tumor/cancer or metastatic tumor/cancer, including solid tumors and hematological tumors.
  20. 如权利要求1-19任意一项所述的方法，其中所述肿瘤/癌症选自：头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经***癌、神经内分泌肿瘤、咽喉癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝细胞瘤、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子***、膀胱癌、***癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、全身性轻链淀粉样变性和梅克尔细胞癌；更优选的，所述淋巴瘤选自：霍奇金淋巴瘤、非霍奇金淋巴瘤、弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤、小淋巴 细胞性淋巴瘤、富含T-细胞/组织细胞的大B-细胞淋巴瘤和淋巴浆细胞性淋巴瘤，所述肺癌选自：非小细胞肺癌和小细胞肺癌，所述白血病选自：慢性髓细胞样白血病、急性髓细胞样白血病、淋巴细胞白血病、成淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和髓样细胞白血病。The method of any one of claims 1-19, wherein the tumor/cancer is selected from the group consisting of head and neck squamous cell carcinoma, head and neck cancer, brain cancer, glioma, glioblastoma multiforme Cell tumor, neuroblastoma, central nervous system cancer, neuroendocrine tumor, throat cancer, nasopharyngeal cancer, esophageal cancer, thyroid cancer, malignant pleural mesothelioma, lung cancer, breast cancer, liver cancer, hepatoma, liver and gallbladder cancer, Pancreatic cancer, stomach cancer, gastrointestinal cancer, bowel cancer, colon cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, Skin cancer, melanoma, leukemia, lymphoma, bone cancer, chondrosarcoma, myeloma, multiple myeloma, myelodysplastic syndrome, myeloproliferative neoplasms, squamous cell carcinoma, Ewing's sarcoma, systemic light chain Amyloidosis and Merkel cell carcinoma; more preferably, the lymphoma is selected from: Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, original Episodic mediastinal large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, T-cell/histiocytic-rich large B-cell lymphoma, and lymphoplasmacytic lymphoma, the lung cancer being selected from the group consisting of : non-small cell lung cancer and small cell lung cancer, the leukemia is selected from the group consisting of: chronic myeloid leukemia, acute myeloid leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia and myeloid leukemia.
  21. 一种药物组合物和/或药物组合，其包含PI3K抑制剂、溶瘤病毒和PD-1抑制剂，以及可药用载体。A pharmaceutical composition and/or pharmaceutical combination, which comprises a PI3K inhibitor, an oncolytic virus and a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
  22. 如权利要求21所述的药物组合物和/或药物组合，其中所述PI3K抑制剂选自PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ亚型抑制剂。The pharmaceutical composition and/or pharmaceutical combination according to claim 21, wherein the PI3K inhibitor is selected from PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ subtype inhibitors.
  23. 如权利要求21或22所述的药物组合物和/或药物组合，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003和其任意组合。The pharmaceutical composition and/or pharmaceutical combination as claimed in claim 21 or 22, wherein the PI3K inhibitor is selected from Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leniolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib, Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003 and any combination thereof.
  24. 如权利要求21-23任意一项所述的药物组合物和/或药物组合，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-23, wherein the PI3K inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022104040-appb-100002
    Figure PCTCN2022104040-appb-100002
  25. 如权利要求21-24任意一项所述的药物组合物和/或药物组合，其中所述溶瘤病毒包括天然存在的、经过修饰的和经过重组的具有复制能力，并且能够侵染和裂解肿瘤细胞的病毒。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-24, wherein the oncolytic virus includes naturally occurring, modified and recombinant viruses capable of infecting and lysing tumors Cell virus.
  26. 如权利要求21-25任意一项所述的药物组合物和/或药物组合，其中溶瘤病毒选自呼肠病毒(reovirus)，新城疫病毒(Newcastle disease virus)，水泡性口炎病毒(vesicular stomatitis virus)，腺病毒(adenovirus)，痘苗病毒(vaccinia virus)， 滤过性病毒(parapox orf virus)，辛德比斯病毒(Sindbis virus)和单纯疱疹病毒(herpes simplex virus)。The pharmaceutical composition and/or pharmaceutical combination as claimed in any one of claims 21-25, wherein the oncolytic virus is selected from reovirus (reovirus), Newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus, adenovirus, vaccinia virus, parapox orf virus, Sindbis virus and herpes simplex virus.
  27. 如权利要求21-26任意一项所述的药物组合物和/或药物组合，其中所述PD-1抑制剂选自：抗PD-1抗体、抗PD-L1抗体和抗PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗和其任意组合物。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-26, wherein the PD-1 inhibitor is selected from: anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody; Preferably, wherein the PD-1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimab, Sintilimumab, Tislelizumab, Karelizumab and any combination thereof.
  28. 如权利要求21-27任意一项所述的药物组合物和/或药物组合，其中所述PI3K抑制剂、溶瘤病毒和PD-1抑制剂可以处于同一和/或分开的剂型(dosage form)中。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-27, wherein the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be in the same and/or separate dosage form (dosage form) middle.
  29. 如权利要求21-28任意一项所述的药物组合物和/或药物组合，其中所述PI3K抑制剂可以配制成以经口服、***或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-28, wherein the PI3K inhibitor can be formulated into a dosage form that is taken orally, buccally, or via an extradigestive route, such as the oral route Dosage forms can be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example, dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, The dosage forms for subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, percutaneous penetration and transmucosal administration can be, for example, solution, powder injection or lyophilized preparation.
  30. 如权利要求21-29任意一项所述的药物组合物和/或药物组合，其中以经口服、***或经消化道外途径的剂型施用所述溶瘤病毒，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-29, wherein the oncolytic virus is administered in a dosage form of oral, buccal or parenteral route, for example, the dosage form of the oral route can be are tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, for example the dosage form for the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, Intramuscular, intracranial, intrathecal, intratumoral, transdermal, transmucosal dosage forms.
  31. 如权利要求21-30任意一项所述的药物组合物和/或药物组合，其中所述PD-1抑制剂可以配制成以消化道外途径施用的剂型，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药，例如可以是溶液剂、粉针剂或冻干剂。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-30, wherein the PD-1 inhibitor can be formulated into a dosage form administered by an extradigestive route, for example, the extradigestive route can be intravenous , intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal, transmucosal administration, such as solution, powder injection or lyophilized preparation.
  32. 如权利要求21-31任意一项所述的药物组合物和/或药物组合，其中每单位剂型(unit dosage form)中包含1-1000mg剂量的PI3K抑制剂，例如所述剂量为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、 30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000mg或以上任意两个数值之间的值。The pharmaceutical composition and/or pharmaceutical combination as claimed in any one of claims 21-31, wherein each unit dosage form (unit dosage form) comprises the PI3K inhibitor of 1-1000mg dose, for example, said dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000 mg or a value between any two values above.
  33. 如权利要求21-32任意一项所述的药物组合物和/或药物组合，其中每单位剂型(unit dosage form)中包含约10 2PFU至约10 17PFU剂量的溶瘤病毒，例如所述剂量为10 2、10 3、10 4、10 5、10 6、10 7、10 8、10 9、10 10、10 11、10 12、10 13、10 14、10 15、10 16、10 17PFU或以上任意两个数值之间的值。 The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-32, wherein each unit dosage form (unit dosage form) contains about 10 2 PFU to about 10 17 PFU doses of oncolytic virus, such as the Dose is 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 , 10 15 , 10 16 , 10 17 PFU or a value between any two of the above values.
  34. 如权利要求21-33任一项所述的药物组合物和/或药物组合，其中每单位剂型中包含1-5000mg剂量的PD-1抑制剂，例如所述剂量为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000、1100、1200、1300、1400、1500、1600、1700、1800、1900、2000、2200、2400、2500、2600、2700、2750、2800、3000、3500、4000、4500、5000mg或以上任意两个数值之间的值。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-33, wherein each unit dosage form comprises a PD-1 inhibitor in a dose of 1-5000 mg, for example, the dose is 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80 ,90,100,110,120,125,130,140,150,160,170,175,180,190,200,250,300,350,400,450,500,600,700,750,800,900 , 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2500, 2600, 2700, 2750, 2800, 3000, 3500, 4000, 4500, 5000 mg or any two of the above value between values.
  35. 如权利要求21-34任意一项所述的药物组合物和/或药物组合，其用于***/癌症和/或产生针对肿瘤/癌症的记忆免疫应答。The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-34, which is used for treating tumor/cancer and/or generating memory immune response against tumor/cancer.
  36. 如权利要求21-34任意一项所述的药物组合物和/或药物组合用于制备***/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的药物的用途。Use of the pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-34 for preparing a medicine for treating tumor/cancer and/or generating memory immune response against tumor/cancer.
  37. 一种药盒，其包含权利要求21-35任意一项所述的药物组合物和/或药物组合，以及使用说明，其中所述PI3K抑制剂、溶瘤病毒和PD-1抑制剂可以处于同一和/或分开的容器中。A kit comprising the pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-35, and instructions for use, wherein the PI3K inhibitor, oncolytic virus and PD-1 inhibitor can be in the same and/or in a separate container.
PCT/CN2022/104040 2021-07-13 2022-07-06 Combined therapy for treating cancer WO2023284597A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280013623.5A CN116887837A (en) 2021-07-13 2022-07-06 Combination therapy for the treatment of cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110791354.2 2021-07-13
CN202110791354.2A CN115607678A (en) 2021-07-13 2021-07-13 Combination therapy for the treatment of cancer

Publications (1)

Publication Number Publication Date
WO2023284597A1 true WO2023284597A1 (en) 2023-01-19

Family

ID=84856157

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/104040 WO2023284597A1 (en) 2021-07-13 2022-07-06 Combined therapy for treating cancer

Country Status (3)

Country Link
CN (2) CN115607678A (en)
TW (1) TW202317134A (en)
WO (1) WO2023284597A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107001478A (en) * 2014-10-14 2017-08-01 诺华股份有限公司 Antibody molecule for PD L1 and application thereof
CN108025051A (en) * 2015-07-29 2018-05-11 诺华股份有限公司 Include the conjoint therapy of anti-PD-1 antibody molecules
CN108495651A (en) * 2015-12-17 2018-09-04 诺华股份有限公司 The antibody molecule and application thereof of anti-PD-1
CN108686221A (en) * 2018-07-25 2018-10-23 广州威溶特医药科技有限公司 The antitumor drug of synergy
WO2021116943A1 (en) * 2019-12-12 2021-06-17 Ignite Immunotherapy, Inc. Variant oncolytic vaccinia virus and methods of use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107001478A (en) * 2014-10-14 2017-08-01 诺华股份有限公司 Antibody molecule for PD L1 and application thereof
CN108025051A (en) * 2015-07-29 2018-05-11 诺华股份有限公司 Include the conjoint therapy of anti-PD-1 antibody molecules
CN108495651A (en) * 2015-12-17 2018-09-04 诺华股份有限公司 The antibody molecule and application thereof of anti-PD-1
CN108686221A (en) * 2018-07-25 2018-10-23 广州威溶特医药科技有限公司 The antitumor drug of synergy
WO2021116943A1 (en) * 2019-12-12 2021-06-17 Ignite Immunotherapy, Inc. Variant oncolytic vaccinia virus and methods of use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALAGESAN BRINDA, CONTINO GIANMARCO, GUIMARAES ALEXANDER R., CORCORAN RYAN B., DESHPANDE VIKRAM, WOJTKIEWICZ GREGORY R., HEZEL ARAM: "Combined MEK and PI3K Inhibition in a Mouse Model of Pancreatic Cancer", CLINICAL CANCER RESEARCH, ASSOCIATION FOR CANCER RESEARCH, US, vol. 21, no. 2, 15 January 2015 (2015-01-15), US, pages 396 - 404, XP093024641, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-14-1591 *
DEVALINGAM MAHALINGAM, WILKINSON GREY A., ENG KEVIN H., FIELDS PAUL, RABER PATRICK, MOSELEY JENNIFER L., CHEETHAM KAROL, COFFEY MA: "Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study", CLINICAL CANCER RESEARCH, VOL. 26, N. 1, 1 January 2020 (2020-01-01), pages 71 - 81, XP055732456, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942612/pdf/nihms-1541241.pdf> [retrieved on 20200921], DOI: 10.1158/1078-0432.CCR-19-2078 *

Also Published As

Publication number Publication date
CN115607678A (en) 2023-01-17
TW202317134A (en) 2023-05-01
CN116887837A (en) 2023-10-13

Similar Documents

Publication Publication Date Title
TWI764943B (en) Combination use of anti-pd-1 antibody and vegfr inhibitor in the preparation of a medicament for the treatment of cancer
EP3923941A1 (en) Pharmaceutical combination comprising tno155 and ribociclib
WO2022111714A1 (en) Combination therapy for treating pik3ca-mutated cancer
CN106572993A (en) Combination therapies for the treatment of cancer
PT1339458E (en) Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity
DK2605764T3 (en) Compositions for the treatment of cancer
US11602533B2 (en) Crenolanib combination therapy
CN105338980A (en) Pharmaceutical combinations
JP2023542093A (en) Use of thiauranib in combination with immune checkpoint inhibitors in antitumor therapy
AU2016297555A1 (en) Methods for treating cancer using apilimod
JP2023109899A (en) Combinations comprising at least one spliceosome modulator and at least one inhibitor selected from bcl2 inhibitors, bcl2/bclxl inhibitors and bclxl inhibitors and methods of use
SG187828A1 (en) Novel combination therapy for the treatment of cancer
WO2020249018A1 (en) Combined pharmaceutical composition for treating driver-gene-positive lung cancer
EA020046B1 (en) Pharmaceutical combination
WO2023284597A1 (en) Combined therapy for treating cancer
CN114845720A (en) Once daily cancer treatment regimen using PRMT5 inhibitors
WO2020236668A1 (en) Leukadherin-1 alone or in combination for use in the treatment of cancer
US20210353648A1 (en) Grapiprant unit dosage forms
CN105916517A (en) Pharmaceutical composition for treatment or palliation of elderly or end-stage cancer patient
JP7381115B2 (en) Compositions and their application in the preparation of medicines for cancer treatment
JP2016520662A (en) Pharmaceutical combination of PI3K inhibitor and microtubule destabilizer
CN114728003A (en) Therapeutic combinations of acatinib and caspasertinib for the treatment of B-cell malignancies
BR112021008606A2 (en) use of tivozanib to treat individuals with refractory cancer
US20230338574A1 (en) Antibody-nanoparticle complexes and methods for making and using the same
AU2021320130A1 (en) Treatment of CLL

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22841234

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280013623.5

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE