CN117425492A - Administration of bispecific T cell cement - Google Patents
Administration of bispecific T cell cement Download PDFInfo
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- CN117425492A CN117425492A CN202280034812.0A CN202280034812A CN117425492A CN 117425492 A CN117425492 A CN 117425492A CN 202280034812 A CN202280034812 A CN 202280034812A CN 117425492 A CN117425492 A CN 117425492A
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Abstract
Methods for reducing myelogenous suppressor cells and activating T cells in a patient and for treating a patient having a solid tumor are described. The method requires the administration of CD3/CD33T cell cement.
Description
Cross Reference to Related Applications
The present application claims the benefit of U.S. provisional application No. 63/173,224, filed on 9 at 4/2021, the entire contents of which are incorporated herein by reference.
Background
T cell cement, a specific class of bispecific antibodies, mediate binding between target cells and T cells, resulting in T cell directed lysis and T cell activation, differentiation and proliferation. While T cell cements have shown impressive efficacy and anti-tumor activity in some circumstances, in many cases, a barrier to wider therapeutic success is the undesirable activity against normal cells expressing the target of interest. This "on-target, off-tumor" toxicity can be significant and has been widely reported for engineered T cell cements.
Myeloid-derived suppressor cells (MDSCs) act locally and systemically to impair anti-tumor immunity, thereby suppressing effector T cell responses, promoting the formation of immunosuppressive regulatory T cells, suppressing maturation and antigen presentation of dendritic cells, and promoting the formation of metastases. MDSCs elicit a range of inhibitory functions that suppress normal T cell responses and elicit non-responsiveness to immune checkpoint blockade. The primary function of MDSCs is to inhibit T cell activity in a variety of ways, both pathologically and environmentally dependent. The presence of MDSCs is believed to be associated with adverse outcomes and lack of response to certain therapies (e.g., therapies that activate T cells and therapies that involve the use of checkpoint inhibitors).
Some T cell activation therapies (e.g., immunotherapy, such as T cell cement and CAR T cell therapy) are associated with Cytokine Release Syndrome (CRS). The occurrence of CRS may limit the utility of some immunotherapies. T cell activation drives bone marrow cell activation and production of various cytokines and chemokines, including IL-6. In some cases, the levels of cytokines and chemokines are pathological. MDSC belongs to bone marrow cells that are the primary producer of IL-6.
Disclosure of Invention
Described herein are methods for using AMV564, a bispecific bivalent molecule that binds to CD3 and CD 33. AMV564 is a homodimeric protein (i.e., a homodimer of a polypeptide having the amino acid sequence of SEQ ID NO: 1) having four single chain variable fragment (scFv) binding sites, two of which bind CD33 and two of which bind CD3. In theory, the bivalent design may restore selectivity to the T cell cement, leading to its preferential binding to regions of high local target density, such as those found at active signaling sites or associated with high receptor density or expression. Although AMV564 binds CD33 (which is widely expressed across the medullary system), it can be administered in a manner that provides the desired therapeutic index, while selectively binding MDSCs. Importantly, AMV564 has been found to be selective over a wide dose range. Without being bound by any particular theory, this may be due to some combination of: bivalent, affinity of scFv and homodimeric geometry. For example, again without being bound by any particular theory, the structure of AMV564 may allow it to bind to the dimerized CD33 cluster.
AMV564 has dual activity: it induces T cell-mediated MDSC killing and drives T cell activation, thereby promoting favorable polarization (e.g., th1 CD 4T cells and effector CD 8T cells). The EC50 of AMV564 for MDSCs is less than about 3pM. With proper administration, AMV564 largely salvages neutrophils, monocytes, and many differentiated myeloid cells while directly killing MDSCs, thereby inhibiting MDSC-driven inhibitory pathways.
AMV564 can be used to reduce MDSC and can be used to reduce systemic immunosuppression, for example, in patients with solid tumors. AMV564 may also be used in combination with various immunotherapies to control CRS and reduce immunosuppression.
Peripheral MDSCs may play an important role in T cell inhibition and T cell trafficking to tumor sites, both of which are potential rate limiting factors for therapies based on T cell activation. For example, in some cases, a 15 μg dose of AMV564 may achieve significant depletion of MDSC populations. When MDSCs are recruited from bone marrow, peripheral depletion can be adequately controlled over a dosing time frame that exceeds the limited lifetime of tissue resident MDSCs to benefit anti-tumor immunity. However, the distribution of AMV564 in the tumor microenvironment may target MDSCs at tumor sites while promoting local T cell expansion. In addition, delivery or entry of AMV564 into draining lymph nodes other than the outer periphery (e.g., via the CIV pathway, up to doses of 50, 75, and 100 μg) may deregulate anti-tumor T cells and restore antigen presentation and immune homeostasis. Subcutaneous delivery of AMV564 (e.g., at doses of 5, 15, or 50 μg) provides a direct mechanism for initial distribution in the lymphatic system, including tumor draining lymph nodes. Subcutaneous administration of AMV564 was effective at lower doses, possibly due to proximity to the lymphatic system.
AMV564 may alleviate immunosuppression and activate T cell effector functions in cancer patients. AMV564 may alleviate immunosuppression by targeted depletion of Myeloid Derived Suppressor Cells (MDSCs) and by direct activation/repolarization of T cells and enhancement of T effector function.
Importantly, subcutaneous administration of AMV564 promotes immune activation by targeting the lymphatic system.
Described herein is a method for reducing myelogenous suppressor cells and activating T cells in a patient (e.g., a patient undergoing immunotherapy) comprising administering to the patient AMV564 (a polypeptide having the amino acid sequence of SEQ ID NO: 1). In various embodiments: AMV564 was administered by subcutaneous injection; the dose of AMV564 injected is 5-150 μg (micrograms); AMV564 is administered for at least 7 days (8, 9, 10, 11, 12, 13, or 14 days) over a period of 14 days; AMV564 is administered subcutaneously daily (e.g., at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 μg/dose); AMV6564 was administered for 10 days over a period of 14 days; AMV6564 was administered twice in consecutive 5 days over a period of 14 days; AMV6564 was administered for 5 consecutive days, followed by two days without administration, and followed by 5 consecutive days; AMV564 is administered over a 21 day period, wherein AMV564 is administered for at least 7 days over a 14 day period and not administered for a subsequent 7 day period; repeating the 21-day cycle at least twice; AMV564 was administered for a period of 14 days for at least 10 days, with 5 consecutive days, then 2 days without, then 5 consecutive days; when administered, the dose of AMV564 administered daily was 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 μg; treating a patient with a T cell activating therapy (e.g., the therapy is CAR T cell therapy; the therapy is CTL therapy; the therapy is antibody therapy; the therapy is treatment with a T cell cement comprising a CD3 binding domain and activating T cells); the patient is suffering from leukemia (acute myelogenous leukemia or myelodysplastic syndrome) or is receiving leukemia treatment; the patient is suffering from or being treated for a solid tumor; the solid tumor is selected from the group consisting of: pancreatic cancer, ovarian cancer, colon cancer, rectal cancer, non-small cell lung cancer, urothelial cancer, squamous cell carcinoma, rectal cancer, penile carcinoma, endometrial carcinoma, small intestine cancer, appendiceal cancer; administration of the AMV564 achieves a steady state exposure of 0.1-5pM (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 pM) of the AMV 564.
Also described is a method for treating a solid tumor in a patient, the method comprising administering AMV564 (a polypeptide having the amino acid sequence of SEQ ID NO: 1) to the patient. In various embodiments: AMV564 was administered by subcutaneous injection; the dose of AMV564 injected is 5-150 μg (mcg or micrograms); AMV564 is administered for at least 7 days (8, 9, 10, 11, 12, 13, or 14 days) over a period of 14 days; AMV564 is administered subcutaneously daily (e.g., at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 μg/dose); AMV6564 was administered for 10 days over a period of 14 days; AMV6564 was administered twice in consecutive 5 days over a period of 14 days; AMV6564 was administered for 5 consecutive days, followed by two days without administration, and followed by 5 consecutive days; AMV564 is administered over a 21 day period, wherein AMV564 is administered for at least 7 days over a 14 day period and not administered for a subsequent 7 day period; repeating the 21-day cycle at least twice; AMV564 was administered for a period of 14 days for at least 10 days, with 5 consecutive days, then 2 days without, then 5 consecutive days; when administered, the dose of AMV564 administered daily was 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 μg; treating a patient with a T cell activating therapy (e.g., the therapy is CAR T cell therapy; the therapy is CTL therapy; the therapy is antibody therapy; the therapy is treatment with a T cell cement comprising a CD3 binding domain and activating T cells); the patient is suffering from leukemia (acute myelogenous leukemia or myelodysplastic syndrome) or is receiving leukemia treatment; the patient is suffering from or being treated for a solid tumor; the solid tumor is selected from the group consisting of: pancreatic cancer, ovarian cancer, colon cancer, rectal cancer, non-small cell lung cancer, urothelial cancer, squamous cell carcinoma, rectal cancer, penile carcinoma, endometrial carcinoma, small intestine cancer, appendiceal cancer; administration of AMV564 achieves a steady state exposure of 0.1-5pM AMV564; the solid tumor is selected from the group consisting of: small Cell Lung Cancer (NSCLC) (e.g., metastatic non-squamous NSCLC, III NSCLC, metastatic NSCLC expressing PD-L1), melanoma, mecell cells, microsatellite highly unstable cancer (e.g., unresectable or metastatic, microsatellite highly unstable (MSI-H) or mismatch repair deficient); patients progressed after checkpoint blockade; administration of AMV564 achieves a steady state exposure of 0.1-5pM AMV564; the method comprises administering 5-50 μg AMV564 by continuous intravenous infusion.
Also described is a method for treating AML by administering AMV564 to achieve steady state exposure of 30-70pm AMV 564.
CD33, also known as Siglec-3, is a transmembrane protein expressed on myeloid cells. CD33 has long been considered an attractive target for Acute Myelogenous Leukemia (AML) due to its high incidence and high expression on leukemic blast cells. The function of CD33 is not fully understood, but activation of CD33 signaling on early lineage myeloid cells, such as immunosuppressive myeloid-derived suppressor cells (MDSCs), has been demonstrated to result in expansion of MDSCs and production of inhibitory cytokines and factors. CD33 expression is used as a component of a cell surface marker panel to identify these immunosuppressive monocytes and granulocytes (e.g., by using flow cytometry for cellular immunophenotyping). It is not clear what, if any, CD33 plays a role in the differentiation of mature monocytes, neutrophils, macrophages and dendritic cells into higher grade myeloid cells. Indeed, the use of CRISPR techniques to knock out CD33 in human cells has demonstrated that CD33 is not essential for lineage differentiation, but it still continues to be expressed at different levels on most of these cells, making it a challenging target for non-selective T cell binding agents in terms of safety and efficacy.
T cell cements function by: acting as a bridge between the antigen on the target cell and the different antigens on the T cell, a ternary complex is formed between the drug and the two different cell types, mimicking the formation of a natural T cell-target cell synapse generated during an adaptive immune response. It is believed that 10-100 drug molecules must be properly bound in order to activate T cell killing, and T cells must also be available. Thus, this active state gives additional considerations for receptor occupancy and dosing beyond a standard model of inhibiting ligands or receptors, for example, by biopharmaceutical binding, where dosing strategies aim to maximize target coverage until unacceptable toxicity is reached. There are still more factors to consider for T cell cements targeting widely expressed antigens such as CD 33. In addition to the potential safety risks associated with the extensive depletion of myeloid cells (which provide valuable protection against infection), such cell populations can be very large (e.g., up to 1000 hundred million neutrophils per day in humans), and thus efficacy can be compromised due to inadequate drug distribution and insufficient T cell supply to accomplish killing. Thus, targeted therapy of other cell populations (such as leukemia blasts or more rarely immunosuppressive MDSCs) may be hindered due to the widespread distribution of drugs in CD33 positive normal bone marrow cells, and the need for sufficient relevant T cells to achieve killing. For these reasons, determining the proper dosage of T cell cement, dosing schedule and route of administration is an exceptionally difficult task, with difficulties far exceeding that of monovalent, monospecific agents.
Binding properties and dose selection of AMV564
The divalent design of the AMV564 is reflected in its physical properties. AMV564 is very potent and exhibits cell killing at low receptor occupancy, where depletion of CD33 target cells exhibits picomolar or sub-picomolar EC50 values ex vivo or in vitro. AMV564 is a potent agonist that can elicit biological activity at low receptor occupancy or low target binding levels. Binding studies using flow cytometry showed that neutrophils, polymorphonuclear (PMN) leukocytes or monocytes did not bind at 1 or 10pM amv564, in contrast MDSC and leukemia blast line KG1 bound effectively at both 1 and 10pM (fig. 1F-1G). AMV564 appeared to be highly selective for MDSCs at concentrations of 1 and 10pM compared to other abundant CD33 expressing cells.
Thus, when the binding of AMV564 to the target cells is sufficient to generate activity, but minimal binding to other bone marrow cells, an optimal therapeutic window is obtained that combines safety with anti-tumor (e.g., leukemia blast) and/or anti-suppressor cell (MDSC) activity. In addition to safety considerations, excessive engagement of large cell populations encompassing the normal myeloid lineage may lead to reduced efficacy due to poor drug distribution and insufficient T cells available to achieve the necessary ternary complex formation to mimic natural T cell synapses to promote cell killing.
Depletion and dose selection of MDSCs
Overcoming the inhibitory tumor microenvironment is a major challenge in immunotherapy. The key cellular effectors of the inhibitory tumor microenvironment are MDSCs, which are associated with immune dysfunction, inhibition of anti-tumor immunity, and adverse responses to immunotherapy. MDSCs suppress T cell and NK cell responses by a variety of cytokines, actives and pathways. In addition, they inhibit the efficient antigen presentation of dendritic cells in tumor draining lymph nodes. In another aspect of the disclosure, AMV564 depletes MDSCs in the periphery and bone marrow of AML patients at low doses. The rapid decrease observed at low introduction doses of AMV546 indicated effective binding and depletion of monocyte and granulocyte MDSC populations. MDSCs are rare in the periphery of healthy adults and are significantly elevated in cancer patients. However, they are still relatively rare cells compared to the usually mature myeloid lineage, and their efficacy of depletion and control may be reduced at higher doses when overall receptor occupancy is detrimental to selectivity for divalent T cell cements (such as AMV 564).
AMV564 administered at a dose of 5-50 μg to generate a near steady state exposure in the range of 0.1-5pM in solid tumor patients can effectively deplete MDSCs and promote favorable CD4 and CD 8T cell activation profiles and cytokine environments to promote recovery of anti-tumor immunity. Higher doses of 50-75 μg or 75-150 μg will also result in exposures that remain within the selective range of MDSC depletion.
Circulating MDSCs are pharmacodynamic biomarkers of AMV564 and T cell responses. Since MDSCs are known to be induced by T cell activation, they are the result of AMV564 stimulating T cell activation. MDSCs reflect engagement of AMV564 with target cells (MDSCs) and depletion of such cells, and for doses of bivalent, bispecific T cell cement such as AMV564, they reflect effective dosing within the optimal therapeutic index range of drugs to enable effective depletion of these relatively rare cells compared to the rest of the CD33 positive myeloid lineage.
Because AMV564 depletes MDSCs, treatment with AMV564, e.g., under the dosing regimen described herein, can be used to deplete MDSCs in a variety of circumstances. For example, AMV564 may be used to deplete MDSCs in patients treated with activated T cells or therapies involving administration of activated T cells.
Management of Cytokine Release Syndrome (CRS)
CRS, while not fully understood, appears to be involved in T cell activation and subsequent activation of macrophages and other bone marrow cells to produce and secrete IL-6, IL-1B and other cytokines. CRS is typically associated with T cell engagement therapies (such as T cell engagement bispecific antibodies and CAR-T therapies). CRS was most pronounced at the beginning of dosing. As shown below, administration of AMV564 via the subcutaneous route at a dose of, for example, 15-50 μg in solid tumor patients resulted in robust T cell activation, as assessed by various metrics, including up to a 10-40 fold increase in outer Zhou Ganrao-prime gamma (ifnγ) detectable in the first dosing cycle relative to baseline. However, the increase in IL-6 was relatively modest (about 1:1 for both cytokines, or favoring higher IFNγ) (see FIGS. 7A-7E), and IL-1B was not detected at significant levels. This beneficial profile is consistent with the patient's lack of CRS observed in this clinical study. This favorable profile of significantly strong activation of T cells without CRS may reflect a combination of features including depletion of MDSCs (which may produce inflammatory cytokines), bivalent T cell engagement of AMV564 (which may more closely resemble more primitive T cell receptor engagement), and lymphatic delivery and distribution kinetics associated with subcutaneous injection of AMV 564. AMV564 has an advantageous therapeutic index for long-term administration, and these properties should also help to reduce CRS after the completion of the introduced administration to achieve the target dose.
Combination therapy
Effective treatment of tumorigenesis is typically achieved by combination therapy. The functional therapeutic index of AMV564, along with the dose range that maximizes both efficacy and safety (notably, without significant depletion of normal bone marrow cells), makes it well suited for combination therapy methods. In solid tumors, combination strategies include, but are not limited to, checkpoint blockade (PD-1 or PDL-1 blockers), T-cell activators and bulking agents (such as cytokines IL-2, IL-10, and IL-15), dual targeting agents such as those targeting checkpoints (e.g., PD-1 or PDL-1) and immunosuppression (e.g., tgfβ), CAR therapy (expressed in T cells or NK cells), NK activation therapy, or standard-of-care chemotherapy. In AML and MDS, the previously listed therapies may also be used in combination with other established agents in AML, such as hypomethylating agents (e.g., azacytidine, decitabine), differentiating agents (e.g., targeting IDH 1/2), targeting agents (e.g., for FLT 3), agents targeting anti-apoptotic proteins such as BCL2 (e.g., valnemtock), BCL-XL or MCL1, or lenalidomide.
AMV564 may be used alone or in combination to treat melanoma (e.g., a patient with unresectable or metastatic melanoma, melanoma involving lymph nodes after complete excision); non-small cell lung cancer (NSCLC) (e.g., metastatic non-squamous NSCLC, III NSCLC, metastatic NSCLC expressing PD-L1); head and Neck Squamous Cell Carcinoma (HNSCC); classical hodgkin lymphoma (cHL); primary mediastinum large B-cell lymphoma (PMBCL); urothelial cancer (e.g., locally advanced or metastatic urothelial cancer expressing PD-L1); microsatellite highly unstable cancers (e.g., unresectable or metastatic, microsatellite highly unstable (MSI-H) or mismatch repair deficient); solid tumors that progressed after past treatment; breast cancer, uterine cancer, gastric cancer (e.g., recurrent locally advanced or metastatic gastric cancer expressing PD-L1 or esophageal-gastric junction adenocarcinoma); cervical cancer; hepatocellular carcinoma (HCC); merkel Cell Carcinoma (MCC); and Renal Cell Carcinoma (RCC).
Drawings
The data presented in FIGS. 1A-1G show that AMV264 depletes MDSC and activates T cells ex vivo, and AMD564 binds MSC and KG-1 cells at 1 and 10pm, but does not bind monocytes at these concentrations. Figure 1A shows that treatment of PBMCs with CD33 ligand S100A9 resulted in MDSC amplification and increased CD33 expression. Figures 1B-1E show that exposure to AMV564 counteracts Reactive Oxygen Species (ROS) generated in response to S100A9 stimulation of PBMCs to amplify MDSCs (figure 1B), resulting in selective depletion of MDSCs (figure 1C), and increased numbers and activation states of CD 8T cells (figure 1D) and CD 4T cells (figure 1E) (as assessed by ifnγ positive fractions).
Figures 2A-2F show that AMV564 treatment resulted in depletion of peripheral blood and myeloid MDSCs and AML blasts without a decrease in neutrophils. Figures 2A and 2B show MDSC depletion in peripheral blood. Figure 2C shows MDSC depletion in bone marrow. FIGS. 2E-2G show the effect of AMV564 treatment on peripheral blood T cells (FIG. 2E), peripheral blood neutrophils (FIG. 2F), and peripheral blood fibroblasts (FIG. 2G). The light bars represent days of dose introduction, and the dark bars represent days of target dose.
Figures 3A-3C present data showing the effect of AMV564 on peripheral blood MDSC, myeloid MDSC, peripheral blood T cells. Fig. 3A shows the effect of AM564 on the percentage of cd45+ cells in peripheral blood MDSCs. Figure 3B shows the effect of AM564 on the percentage of cd45+ cells in bone marrow MDSCs. Fig. 3C shows the effect of AM564 on the percentage of cd45+ cells in peripheral blood T cells. The light bars represent days of dose introduction, and the dark bars represent days of target dose.
The data presented in fig. 4A-4D show that AMV564 is a selective and potent conditional agonist. The single open circles and triangles show the results of CD3/CD28 stimulation in the absence of AMV 564. FIG. 4A shows that AMV564 induced effective dose-dependent cell death of KG1 at a maximum level similar to that of CD3-CD28 stimulation (FIG. 4A). FIG. 4B shows an increase in daughter cells, reflecting that the level of T cell proliferation corresponds to or exceeds the CD3-CD28 reference stimulation. Fig. 4C shows that there is no evidence that AMV564 promotes significant cell death of autologous monocytes or neutrophils. Figure 4D shows that, unlike general T cell stimulation using CD3-CD28, these cell populations do not have any evidence of induction of T cell proliferation.
The data presented in fig. 5A-5E show that MDSC controls are associated with Treg pairs in solid tumor patients. FIGS. 5A-5D show that M-MDSC and G-MDSC are controlled in patients with solid tumors and treated with AMV564 (FIG. 5A: ovarian-15 μg AMV564; FIG. 5B: skin 50 μg AMV564; FIG. 5C: small intestine-15 μg AMV564; FIG. 5D: esophageal-gastric junction-15 μg AMV 564), who are treated with AMV564 (once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle). The filled squares are G-MDSCs and the filled circles are M-MDSCs. Fig. 5E depicts the change in Treg from baseline (B) over two therapy cycles (C1 and C2). Bars on the axis represent days of AMV564 administration.
The data presented in fig. 6A-6G show that the CD8 Treg ratio increases in solid tumor patients after AMV564 treatment. Specifically, FIGS. 6A-6G show an increase in CD8/Treg ratio (on days 1-5 and 8-12 of the 21 day cycle seen with subcutaneous injections once daily (FIG. 6A: small intestine-disease stabilization (15 μg dose), FIG. 6B: ovarian-complete response (15 μg dose), FIG. 6C: GE junction-progressive disease (15 μg dose), FIG. 6D: endometrium-disease stabilization (50 μg dose), FIG. 6E: colorectal-progressive disease (50 μg dose), FIG. 6F: skin-disease stabilization (50 μg dose), FIG. 6G: appendiceal stabilization (50 μg dose)). Dotted lines represent baseline ratios, bars along the x-axis represent days of administration, and broad bars represent ratios of healthy controls whose peripheral blood samples were treated in the same flow-based assay.
The data presented in fig. 7A-7E show that AMV564 promotes favorable CD4 and CD 8T cell polarization (once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle) in ovarian cancer patients administered 15 μg of AMV 564. Figure 7A shows CD8/Treg ratio over 150 days. Figure 7B shows the dynamic modulation of sustained or increased effector CD8 (TBX 21 and/or granzyme B positive) and PD1 positive CD8 fractions. Figure 7C shows dynamic increase of TBX21 positive CD 4T helper cells. Figure 7D shows a sustained increase in T cells. Fig. 7E shows an increase in the percentage of CD 8T cells. The dashed line represents the baseline ratio; bars along the x-axis represent days of dosing and broad bars represent the ratio of healthy controls.
FIGS. 8A-8F show IFNγ cycle 1, IFNγ cycle 2, IL-6 cycle 1, and IL-6 cycle 2 levels in six solid tumor patients treated with AMV564 (patient 1 (FIG. 8A); patient 2 (FIG. 8B); patient 3 (FIG. 8C); patient 11 (FIG. 8D); patient 9 (FIG. 8E); patient 14 (FIG. 8F-cycle 1 only)).
Figures 9A-9D show the results of M-MDSC and G-MDSC measurements in four solid tumor patients treated with AMV564 in combination with palbociclib. Fig. 9A and 9B show observations of solid tumor patients treated with AMV564 once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle, respectively, with 5 μg/day combined pambrizumab (pembrolizumab) administered intravenously at 200mg every 3 weeks (Q3W). Figures 9C and 9D show observations of solid tumor patients treated with AMV564 once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle, respectively, with 15 μg/day in combination with pamo Li Zhushan antibody administered intravenously at 200mg every 3 weeks (Q3W). The filled squares are G-MDSCs and the filled circles are M-MDSCs. Bars on the axis represent days of AMV564 administration.
FIGS. 10A-10D show the effect of AMV564 in combination with Pabo Li Zhushan on T-Bet and granzyme B positive CD8 cells and CD8/Treg ratios in two patients with solid tumors. Fig. 10A and 10C show observations of patient 15 treated with AMV564 (15 μg) in combination with palbociclib (200 mg intravenous administration at Q3W) once daily by subcutaneous injection on days 1-5 and 8-12, respectively, of a 21 day cycle. Fig. 10B and 10D show observations of patient 16 treated with AMV564 (15 μg) in combination with palbociclib (200 mg intravenous administration at Q3W) once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle. The dashed line represents the baseline ratio; bars along the x-axis represent days of AMV564 dosing and broad bars represent the ratio of healthy controls.
Figures 11A-11B show the effect of AMV564 in combination with palbociclizumab treatment on CD8 cell proliferation and activation in two patients with solid tumors. Fig. 11A and 11B show observations of patient 15 (fig. 11A) and patient 16 (fig. 11B) treated with AMV564 (15 μg) in combination with palbociclib (200 mg intravenous administration at Q3W) once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle.
Figures 12A-12B show the effect of AMV564 on M-MDSC cell and G-MDSC cell levels over the course of 5 treatment cycles (< 0.05, < 0.01). FIG. 12A shows the effect on M-MDSC levels of treatment of a solid tumor patient with 15 or 50 μg of subcutaneously administered AMV 564. Figure 12B shows the effect on G-MDSC levels of treatment of solid tumor patients with 15 or 50 μg of subcutaneously administered AMV 564.
Fig. 13A-13B show the effect of AMV564 (alone or in combination with palbociclib) on co-expression of granzyme B and TBX21 on cd8+ T cells (fig. 13A) and on the frequency of granzyme b+cd8+ cells (fig. 13).
FIGS. 14A-14B show the effect of AMV564 (alone or in combination with palbociclib) on IFNγ and IL-6 levels. Fig. 14A shows ifnγ and IL-6 levels observed in solid tumor patients treated with 15 or 50 μg AMV564 (alone or in combination with palbociclizumab, n=11 monotherapy, n=4 combination). Fig. 14B shows that AMV564 exhibited an advantageous ratio of about 1:1 in ifnγ to IL-6 relative to other T cell cements.
Figures 15A-15C show the effect of AMV564 (alone or in combination with palbociclib) on various cytokine levels in patients, as well as in vitro cytotoxicity assays. FIG. 15A shows the effect of AMV564 (alone or in combination with palbociclib) on TNF alpha, IL-1 beta and IL-10 levels in patients. Fig. 15B shows the effect of AMV564 (alone or in combination with palbock mab) on IP-10 (CXCL 10) levels. FIG. 15C shows the results of an AMV564 cytotoxicity assay using KG-1 cells as target cells.
Figures 16A-16C show the effect of AMV564 (alone or in combination with palbociclib) on T cell repertoires in three different patients. Fig. 16A shows expansion of T cell repertoires in patients with small intestine cancer. Fig. 16B shows expansion of T cell repertoires in patients with penile squamous cell carcinoma. Fig. 16C shows expansion of T cell repertoires in patients with pancreatic cancer. Orange circles represent clones that were significantly amplified or were undetectable at baseline.
Figures 17A-17C show the effect of AMV564 on CD8 and CD8 memory cells and T cell rearrangement in ovarian cancer patients diagnosed with RECIST CR. Figure 17A shows that CD8 cells increased during treatment in ovarian cancer patients treated with 15 μg AMV 564. Figure 17B shows that CD8 memory cells increased during treatment in ovarian cancer patients treated with 15 μg AMV 564. Figure 17C shows the tracking of specific T cell rearrangements across treatment time points in ovarian cancer patients.
Detailed Description
AMV564
AMV564 is a homodimer of SEQ ID NO. 1. AMV564 is described in US 9212225 (diabetes 16; SEQ ID NO:113, without 6His tag at the amino terminus) and WO 2016/196230 (SEQ ID NO: 139). A pharmaceutical composition of AMV564 comprises a homodimer of a polypeptide having the amino acid sequence of SEQ ID NO. 1 and a pharmaceutically acceptable carrier or excipient.
AMV564
Example 1: AMV564 depletes MDSC and activates T cells ex vivo
In this study, it was found that ex vivo treatment of primary cells (PBMC, MDS marrow, tumor PBMC) with AMV564 both depletes MDSC and activates T cells. Figure 1A shows that treatment of PBMCs with CD33 ligand S100A9 resulted in MDSC amplification and increased CD33 expression. Exposure to AMV564 counteracts Reactive Oxygen Species (ROS) generated in response to S100A9 stimulation of PBMCs to amplify MDSCs (fig. 1B), resulting in selective depletion of MDSCs (fig. 1C), and increased numbers and activation states of CD 8T cells (fig. 1D) and CD 4T cells (fig. 1E) (as assessed by ifnγ positive fractions).
Thus, ex vivo treatment of Peripheral Blood Mononuclear Cells (PBMCs) from a patient resulted in selective depletion of MDSCs (p < 0.01) and a reduction in reactive oxygen species production. AMV564 induced a significant increase in activated T cells only in the presence of cd33+ target cells, with > 2-fold increase in proliferation of cd4+ and cd8+ T cells. The increase in proliferation is dose dependent and is accompanied by a significant increase in ifnγ production.
AMV564 binds to MDSC (and leukemia blast line KG 1) at 1 and 10pM (FIG. 1F). However, at these concentrations, there is essentially no evidence of monocyte, neutrophil, and polymorphonuclear leukocyte (PMN) binding. These concentrations are in the range of exposure observed with AMV564 administered via the subcutaneous route at a dose of 5-15-50 μg (about 0.1-5 pM). As shown in fig. 1G.
Example 2: AMV564 depletes MDSC and activates T cells in patient
In this clinical study, AMV564 treatment was found to result in depletion of peripheral blood MDSC and myeloid MDSC and AML blast cells, whereas neutrophils were not reduced (fig. 2A-2F). Rapid depletion of monocytes and granulocyte MDSCs is evident with little or no effect on the circulating neutrophils or monocyte populations. Evidence of early T cell activation becomes apparent with rapid redistribution/marginalization of T cells (this apparent transient lymphopenia is the result of T cell activation and migration to lymph nodes and tissues). In FIGS. 2A-2F, lead-in AMV564 administration (15 μg;3 days) is indicated by light bars and target AMV564 administration (100 μg) is indicated by dark bars. In MDSCs, depletion was observed in peripheral blood (fig. 2A and 2B) and bone marrow (fig. 2C). Figures 2D-2E show the effect of AMV564 treatment on peripheral blood T cells, peripheral blood neutrophils and peripheral blood fibroblasts, respectively.
Example 3: MDSC of AMV564 depleted solid tumor patient
In the lead phase dosing (days 1-3 in some patients), an initial increase in peripheral blood MDSC in response to T cell activation was observed (FIGS. 3A-C). Rapid redistribution/marginalization of peripheral blood T cells was also observed during T cell migration to lymph nodes and tissues, consistent with T cell activation (fig. 3C). However, at the target dose, peripheral MDSCs were controlled. Bone marrow MDSC also significantly decreased when assessed relative to baseline on day 15. However, once AMV564 treatment ceases, both bone marrow and peripheral blood MDSCs rebound.
Example 4: AMV564 is a selective and potent conditional agonist
Primary human T cells and KG-1 cells were exposed to AMV564. Target-dependent cytotoxicity (fig. 4A), target-dependent T cell proliferation (fig. 4B), viability of differentiated monocytes and neutrophils (fig. 4C), viability of differentiated monocytes and neutrophils (fig. 4D) were measured, all stimulated with CD3/CD28 as reference T cells. KG1 was used as a surrogate for MDSC in these assays, since KG1 expressed CD33 and AMV564 bound KG1 similarly to MDSC. AMV564 induced potent dose-dependent cell death of KG1 at a maximal level similar to CD3-CD28 stimulation (FIG. 4A). This was accompanied by an increase in daughter cells, which reflects that the level of T cell proliferation was comparable to or exceeded the CD3-CD28 reference stimulation (fig. 4B). However, there is no evidence that AMV564 promoted significant cell death of autologous monocytes or neutrophils (fig. 4C), and similarly, there is no evidence that T cell proliferation was induced with these cell populations (fig. 4D), unlike general T cell stimulation using CD3-CD 28.
Example 5: phase 1 clinical study of AMV564 in patients with solid tumors
This study recruited adult patients with unresectable, advanced metastatic solid tumors that were recurrent and progressive since the last anti-tumor treatment, and no accepted standard treatment exists. The ECOG expression state of the patient is less than or equal to 2, and the organ functions are sufficient. Patients received AMV564 alone (15, 50 or 75 μg/day), or AMV564 (5, 15 or 50 μg/day) in combination with palbociclib (200 mg intravenously administered every 3 weeks (Q3W)). In both cases, AMV564 was administered once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle. AMV564 is well tolerated and pharmacodynamic analysis showed that there is evidence to demonstrate a reduction in immunosuppression (MDSC and Treg reduction) and promotion of effector CD8 and Th1 CD4 responses in the population of stage 1 heterogeneous cancer patients previously treated with other therapies.
In general, patients treated with AMV564 exhibited cytokine profiles consistent with activation of T cells (including CD4 Th1 helper cells, antigen presenting cells), and improved T cell trafficking to tissues such as tumor tissue (increased IFNγ, IL-15, IL-18, soluble granzyme B, and CXCL 10). Although strong T cell activation was observed, there was no onset of cytokine release syndrome.
Example 6: MDSC control in solid tumor patients is associated with Treg control
M-MDSC and G-MDSC were controlled in patients with solid tumors and treated with AMV564 (FIG. 5A: ovary-15 μg AMV564; FIG. 5B: skin 50 μg AMV564; FIG. 5C: small intestine-15 μg AMV564; FIG. 5D: esophageal gastric junction-15 μg AMV 564), who were treated with AMV564 (once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle). Fig. 5E depicts the change in Treg from baseline (B) over two therapy cycles (C1 and C2).
Example 7: increased CD8:Treg ratio in patients with solid tumors following AMV564 treatment
FIGS. 6A-6G show an increase in CD8/Treg ratio observed in most solid tumor patients undergoing AMV564 therapy (FIG. 6A: small intestine-condition stabilization (15. Mu.g dose), FIG. 6B: ovarian-complete response (15. Mu.g dose), FIG. 6C: GE junction-progressive disease (15. Mu.g dose), FIG. 6D: endometrium-condition stabilization (50. Mu.g dose), FIG. 6E: colorectal-progressive disease (50. Mu.g dose), FIG. 6F: skin-condition stabilization (50. Mu.g dose), FIG. 6G: appendiceal condition stabilization (50. Mu.g dose)) by subcutaneous injections once daily on days 1-5 and 8-12 of the 21 day cycle.
Example 8: AMV564 promotes favorable CD4 and CD 8T cell polarization in ovarian cancer patients
Ovarian cancer patients who had previously undergone multiple line platinum-based chemotherapy, surgery, radiation, palbociclizumab (best response was stable, completed 6 months before study initiation) and therapy with nilaparib (nilaparib) and letrozole (letrozole) were treated with 15 μg AMV564 (once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle). As shown in fig. 7A-7E, the patient exhibited a sustained increase in CD8/Treg, an increase in the percentage of CD8, a sustained or increased effect CD8 (TBX 21 and/or granzyme B positive) and dynamic increase in memory CD8 cells, TBX21 positive CD 4T helper cells and dynamic modulation of the PD1 positive CD8 fraction, but no significant overall increase. This patient progressed steadily from disease to partial to complete response at 6-8 week intervals as assessed by CT scan.
Example 9: patients treated with AMV564 showed signs of CRS-free T cell activation
Figures 8A-8F (patients 1, 2, 3, 11, 9 and 14, respectively) show the results of ifnγ and IL-6 measurements in six solid tumor patients treated with AMV564 (once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle). It can be seen that there is clear evidence of systemic ifnγ production without excessive IL-6 production (the ratio of ifnγ to IL-6 for most patients is about 1:1 or better).
In 5 treatment cycles, solid tumor patients (data not shown) exhibited increases in ifnγ, tnfα, and IL18 and other factors at later time points (e.g., end of cycle 2 and cycle 3, cycle 4), consistent with MHC class I upregulation, dendritic cell activation, and T cell trafficking (MDSC-induced factor G-CSF reduction). This same patient had poor CD8/Treg baseline at the time of study entry. Improvements were observed throughout the course of the treatment, particularly around cycle 3, where an increase in CD 8T cell proliferation and activation (Ki 67 and CD38 fractions) was observed, consistent with improvements in CD8 effector functions (T-bet and granzyme B positive fractions). This is consistent with the observed timing of cytokine and factor increases consistent with dendritic cell activation and improvement in Th1 response, suggesting that AMV564, over time, promotes more favorable immune polarization even in this advanced patient.
Example 10: treatment with AMV564 and palbociclizumab
Figures 9A-9D show the results of M-MDSC and G-MDSC measurements in four solid tumor patients treated with AMV564 (5 μg/day (figures 9A and 9B) or 15 μg/day (figures 9C and 9D)) in combination with palbociclib (200 mg intravenously administered every 3 weeks (Q3W)) once daily by subcutaneous injection on days 1-5 and 8-12 of a 21 day cycle. AMV564 days of administration are indicated by bars along the x-axis and palbociclib treatment days are indicated by asterisks. As can be seen, the MDSC was observed to be well controlled.
Figures 10A-10D show data from two patients (figures 10A and 10C: patient 15; figures 10B and 10D: patient 16) treated with AMV564 (15 μg) in combination with palbociclib (200 mg intravenous administration at Q3W) once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle. This data shows evidence of a significant increase in CD8 effector cell fraction and a significant increase in CD8/Treg ratio in cycles 1-2. The data also shows the expansion of T-Bet and granzyme B positive CD8 cells. These effects were not apparent in the 5 μg amv564 combination cohort of this study.
FIGS. 11A-11B show CD 8T cell proliferation data for two patients (FIG. 11A: patient 15; FIG. 11B: patient 16) treated with AMV564 (15 μg) in combination with palbociclib (administered intravenously at Q3W 200 mg) once daily by subcutaneous injection on days 1-5 and 8-12 of the 21 day cycle. This data shows evidence of a significant increase in CD8 proliferation (assessed by CD8 Ki 67) and activation (assessed by CD 8CD 38). Of the 3 patients given in combination, 2 patients increased significantly and rapidly from poor baseline levels, indicating the potential combined benefit of AMV564 and palbociclizumab.
Example 11: AMV564 selectively targets M-MDSC and G-MDSC for depletion and activation of T cells in patients with solid tumors
M-MDSC and G-MDSC were measured in patients with solid tumors treated with 15 or 50 μg of subcutaneously administered AMV 564. As shown in fig. 12A-12B, treatment was associated with a decrease in both MDSC subtypes. This is significant because elevated M-MDSCs are typically associated with lower levels of peripheral T cells.
Treatment of solid tumor patients with AMV564 (alone or in combination with palbockizumab) resulted in increased co-expression of granzyme B and TBX21 (T-bet) on cd8+ T cells (fig. 13A). Furthermore, in patients receiving therapy, the frequency of granzyme b+cd8+ T cells increased significantly between the first and second cycles (fig. 13B).
Example 12: AMV564 induces a modulated immune response
Solid tumor patients treated with 15 or 50 μg of AMV564 (alone or in combination with palbociclizumab, n=11 monotherapy, n=4 combination) exhibited an advantageous ratio of about 1:1 in ifnγ to IL-6 (fig. 14A and 14B). In many cases, treatment with other T cell cements results in a ratio between 0.1 and 0.01.
In solid tumor patients treated with AMV564, the levels of IL-6, IL-1. Beta., IL-10, and TNF. Alpha. (all myelogenous cytokines) remained low (FIG. 15A, FIG. 15B, and data not shown). In contrast, in these patients, levels of pro-inflammatory cytokines that promote Th1 polarization, macrophage activation, and T cell trafficking to tumors were elevated (fig. 15A, 15B, and data not shown).
In vitro cytotoxicity assays using KG-1 cells as target cells demonstrated that AMV564 correlated with favorable ifnγ to IL-6 ratios over a broad range of AMV564 ratios (fig. 15C).
Example 13: AMV564 expansion of peripheral T cell pool
T cell banks of three patients (small intestine cancer, squamous cell carcinoma of the penis, and pancreatic cancer) were evaluated by deep sequencing of TCR beta CDR3 at different treatment cycles (cycle 1, day 1 compared to cycle 2, day 1). Clones that were amplified, restricted or de novo generated at the time of treatment were evaluated to correlate the effect of treatment on TCR repertoire with disease evolution. As shown in fig. 16A-16C, significant expansion of the T cell pool was evident after only one treatment cycle (p=0.008). About 30-over 300 differentially detected T cell clones were observed per patient, including some clones that were undetectable or rare at baseline.
Example 14: expansion of the T cell pool in ovarian cancer patients is associated with increased CD8 memory cells.
Ovarian cancer patients treated with 15 μg AMV564 and diagnosed with RECIST CR exhibited an increase in CD8 cells (fig. 17A) and CD8 memory cells (fig. 17B) during treatment.
Tracking of specific T cell rearrangements across treatment time points showed that several clones expanded and eventually dominated the pool of patients (fig. 17C). Two of the eight maximum expanded T cell clones matched CDR3 sequences consistent with T cells targeting the SLC3A2 neoantigen, which SLC3A2 neoantigen was up-regulated in some cancers and was generally associated with poor prognosis (fig. 17C).
Incorporated by reference
All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
Equivalent scheme
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
Claims (41)
1. A method for treating a patient having a solid tumor, the method comprising administering to the patient an immunotherapy and AMV564, wherein AMV564 is administered before, after, or with the immunotherapy.
2. The method of claim 1, wherein the AMV564 is administered by subcutaneous injection.
3. The method of claim 1, wherein the AMV564 is administered within 4-6 weeks after administration of the immunotherapy.
4. The method of claim 3, wherein the AMV564 is administered for at least 7 days over a period of 14 days.
5. The method of claim 4, wherein the AMV6564 is administered for 10 days over a period of 14 days.
6. The method of claim 5, wherein the AMV6564 is administered twice a consecutive 5 day period for a period of 14 days.
7. The method of claim 5, wherein the AMV6564 is administered for 5 consecutive days, followed by two days without administration, and followed by 5 consecutive days.
8. The method of any of claims 4-7, wherein the AMV564 is administered over a 21 day period, wherein AMV564 is administered for a period of 14 days for at least 7 days and not administered for a subsequent period of 7 days.
9. The method of claim 8, wherein the 21-day cycle is repeated at least twice.
10. The method of claim 9, wherein the AMV564 is administered for at least 10 days over a period of 14 days, wherein 5 days are consecutive, then 2 days are non-administered, then 5 days are consecutive.
11. The method of any one of claims 1-10, wherein the dose of AMV564 administered daily is 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 μg when administered.
12. The method of claim 1, wherein AMV564 is administered at 15 μg/day for 5 days during the first week of therapy and then at 50 μg weekly thereafter.
13. The method of claim 1, wherein AMV564 is administered at 5-50 μg once per week.
14. The method of claim 1, wherein AMV564 is administered at 15 μg/day for 5 days during the first week of therapy and then at 15 μg weekly thereafter.
15. The method of claim 1, wherein AMV564 is administered at 15 μg/day for 5 days during the first week of therapy and then between 15 μg and 50 μg weekly thereafter.
16. The method of any one of claims 1-15, wherein the immunotherapy is CR T cell therapy, CTL therapy, and antibody therapy.
17. The method of claim 1, wherein the solid tumor is selected from the group consisting of breast pancreatic cancer, ovarian cancer, colon cancer, rectal cancer, non-small cell lung cancer, urothelial cancer, squamous cell cancer, rectal cancer, penile cancer, endometrial cancer, small intestine cancer, appendiceal cancer.
18. The method of claim 1, wherein the administration of the AMV564 achieves a steady state exposure of 0.1-5pm AMV 564.
19. The method of claim 1, wherein the administration of the AMV564 achieves a steady state exposure of 0.5-3pm AMV 564.
20. The method of claim 1, wherein the administration of the AMV564 achieves a steady state exposure of 1-5pm AMV 564.
21. The method of claim 1, wherein the immunotherapy is an anti-PD-L1 antibody or an anti-PD-1 antibody.
22. The method of claim 21, wherein the anti-PD-1 antibody is na Wu Shankang, pamil mab or cimiput Li Shan antibody.
23. The method of claim 21, wherein the anti-PD-L1 antibody is alemtuzumab, avilamab, or dimarypo You Shan antibody.
24. The method of claim 1, wherein the immunotherapy is a CAR T cell therapy and AMV564 is administered 1-5 days, 5-10 days, or 5-14 days after administration of the CAR T cell therapy.
25. A method for treating cancer in a patient, the method comprising administering AMV564 to the patient, wherein the cancer does not express CD33.
26. The method of claim 25, wherein the AMV564 is administered by subcutaneous injection.
27. The method of claim 25 or 26, wherein AMV564 is administered at 15 μg/day for 5 days during the first week of therapy and then at 50 μg weekly thereafter.
28. The method of claim 25, wherein AMV564 is administered once per week at 50 μg.
29. The method of claim 25, wherein AMV564 is administered at 15 μg/day for 5 days during the first week of therapy and then at 15 μg weekly thereafter.
30. The method of claim 25, wherein AMV564 is administered at 15 μg/day for 5 days during the first week of therapy and then between 15 μg and 50 μg weekly thereafter.
31. The method of claim 25, wherein the dose of AMV564 injected is 5-50 μg.
32. The method of any one of claims 25-31, wherein the solid tumor is selected from pancreatic cancer, ovarian cancer, colon cancer, rectal cancer, non-small cell lung cancer, urothelial cancer, squamous cell carcinoma, rectal cancer, penile cancer, endometrial cancer, small intestine cancer, and appendiceal cancer.
33. The method of any one of claims 25-31, wherein the solid tumor is selected from small cell lung cancer (NSCLC) (e.g., metastatic non-squamous NSCLC, III NSCLC, metastatic NSCLC expressing PD-L1), melanoma, merkel cell, microsatellite highly unstable cancer (e.g., unresectable or metastatic, microsatellite highly unstable (MSI-H), or mismatch repair deficient); patients who progressed after checkpoint blockade.
34. The method of any one of claims 1-31, wherein the patient has a cancer selected from the group consisting of: melanoma (e.g., patients with unresectable or metastatic melanoma, melanoma involving lymph nodes after complete excision); non-small cell lung cancer (NSCLC) (e.g., metastatic non-squamous NSCLC, III NSCLC, metastatic NSCLC expressing PD-L1); head and Neck Squamous Cell Carcinoma (HNSCC); classical hodgkin lymphoma (cHL); primary mediastinum large B-cell lymphoma (PMBCL); urothelial cancer (e.g., locally advanced or metastatic urothelial cancer expressing PD-L1); microsatellite highly unstable cancers (e.g., unresectable or metastatic, microsatellite highly unstable (MSI-H) or mismatch repair deficient); solid tumors that progressed after past treatment; gastric cancer (e.g., recurrent locally advanced or metastatic gastric cancer expressing PD-L1 or esophageal-gastric junction adenocarcinoma); cervical cancer; hepatocellular carcinoma (HCC); merkel Cell Carcinoma (MCC); and Renal Cell Carcinoma (RCC).
35. A method for expanding T cells, the method comprising culturing the T cells in the presence of AMV 564.
36. The method of claim 35, wherein the T cells express a chimeric antigen receptor.
37. The method of claim 35 or 36, wherein the culturing is continued for at least 5 days.
38. A method for expanding NK cells, the method comprising culturing the NK cells in the presence of AMV 564.
39. The method of claim 38, wherein the NK cells express a chimeric antigen receptor.
40. The method of claim 38 or 39, wherein the culturing is continued for at least 5 days.
41. A method for amplifying cytotoxic lymphocytes (CTLs), the method comprising culturing the CTLs in the presence of AMV 564.
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