Methods of Treating Cancer

Abstract

Provided herein is a method for predicting the effectiveness of cancer therapeutics in a subject.Also disclosed is a method for treating a subject with cancer.Provided herein is a method for treating a subject with cancer, comprising administering a therapeutically effective amount of an immune checkpoint inhibitor to a subject who has previously been identified or diagnosed as having cancer and has previously been identified as having a reduced level of M2 macrophages compared to a reference level. TIFF2025512837000008.tif60128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 324,943, filed March 29, 2022, the contents of which are incorporated herein by reference. Summary of the Invention

[0002] overview Provided herein is a method of treating a subject having cancer, comprising administering a therapeutically effective amount of an immune checkpoint inhibitor to a subject previously identified or diagnosed with cancer, and previously identified as having a reduced level of M2 macrophages compared to a reference level.

[0003] Also provided herein is a method of selecting a pharmaceutical composition comprising an immune checkpoint inhibitor for a subject previously identified or diagnosed with cancer and previously identified as having a reduced level of M2 macrophages compared to a reference level.

[0004] Also provided herein is a method of selecting a subject previously identified or diagnosed with cancer and previously identified as having reduced levels of M2 macrophages, for treatment with a pharmaceutical composition comprising an immune checkpoint inhibitor.

[0005] Also provided herein is a method of predicting the efficacy of treatment with a pharmaceutical composition comprising an immune checkpoint inhibitor in a subject in need thereof, comprising determining that a subject diagnosed or identified as having cancer and identified as having a decreased level of M2 macrophages compared to a reference level is likely to have a positive therapeutic response to treatment with the pharmaceutical composition; or determining that a subject diagnosed or identified as having cancer and identified as having an increased level of M2 macrophages compared to a reference level is unlikely to have a positive therapeutic response to treatment with the pharmaceutical composition.

[0006] In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0007] In some embodiments of any of the methods described herein, the method further includes measuring the level of M2 macrophages in a sample obtained from the subject, and identifying the subject as having an elevated (or elevated) level of M2 macrophages compared to a reference level.

[0008] In some embodiments of any of the methods described herein, the method further includes measuring the level of M2 macrophages in a sample obtained from the subject, and identifying the subject as having a reduced level of M2 macrophages compared to a reference level.

[0009] Also provided herein is a method of treating a subject having cancer by administering a therapeutically effective amount of an anti-ILT4 binding agent to a subject previously identified or diagnosed with cancer, and previously identified as having elevated levels of M2 macrophages compared to a reference level.

[0010] Also provided herein is a method of selecting a pharmaceutical composition comprising an anti-ILT4 binding agent for a subject previously identified or diagnosed as having cancer and previously identified as having elevated levels of M2 macrophages compared to a reference level.

[0011] Also provided herein is a method of selecting a subject previously identified or diagnosed as having cancer and previously identified as having elevated levels of M2 macrophages, for treatment with a pharmaceutical composition comprising an anti-ILT4 binding agent.

[0012] In some embodiments of any of the methods described herein, the anti-ILT4 binding agent is an anti-ILT4 antibody or antigen-binding fragment thereof (e.g., a blocking antibody that interferes with ILT4 / LILRB2 interaction with HLA-G molecules).

[0013] Some embodiments of any of the methods described herein further include administering an immune checkpoint inhibitor to the subject. In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0014] Some embodiments of any of the methods described herein further include measuring the level of M2 macrophages in a sample obtained from the subject, and identifying the subject as having an elevated level of M2 macrophages compared to a reference level.

[0015] In some embodiments of any of the methods described herein, the M2 macrophages have elevated levels of ILT4 expression compared to a reference level.

[0016] In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the level of M2 macrophages in a population of healthy subjects.

[0017] In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 75% percentile of the median level of M2 macrophages number in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 80% percentile of the median level of M2 macrophages in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 85% percentile of the median level of M2 macrophages in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 90% percentile of the median level of M2 macrophages in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 95% percentile of the median level of M2 macrophages in a healthy patient population.

[0018] In some embodiments of any of the methods described herein, the cancer is a solid tumor.In certain embodiments of any of the methods described herein, the solid tumor is non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), small cell lung cancer (SCLC), head and neck cancer, or esophageal cancer.

[0019] In some embodiments of any of the methods described herein, the cancer is a hematological cancer.

[0020] Also provided herein is a method of treating a subject having cancer, comprising administering a therapeutically effective amount of an anti-CCR8 binding agent to a subject previously identified or diagnosed with cancer and previously identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels.

[0021] Also provided herein are methods of selecting a pharmaceutical composition comprising an anti-CCR8 binding agent for a subject previously identified or diagnosed with cancer and previously identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels.

[0022] Also provided herein are methods of selecting a subject previously identified or diagnosed as having cancer, and previously identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels, for treatment with a pharmaceutical composition comprising an anti-CCR8 binding agent.

[0023] Also provided herein is a method of predicting the efficacy of treatment with a pharmaceutical composition comprising an anti-CCR8 binding agent in a subject in need thereof, comprising: determining that a subject diagnosed or identified as having cancer and identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels is likely to have a positive therapeutic response to treatment with the pharmaceutical composition; or determining that a subject diagnosed or identified as having cancer and identified as having elevated levels of Treg cells and decreased levels of NK cells compared to reference levels is unlikely to have a positive therapeutic response to treatment with the pharmaceutical composition.

[0024] In some embodiments of any of the methods described herein, the anti-CCR8 binding agent is an anti-CCR8 antibody or antigen-binding fragment thereof (e.g., a depletion antibody or antigen-binding fragment thereof that has the ability to interfere with ligand binding to CCR8).

[0025] In some embodiments of any of the methods described herein, the method further comprises administering an immune checkpoint inhibitor to the subject. In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0026] In some embodiments of any of the methods described herein, the method further includes measuring the levels of Treg cells and NK cells in a sample obtained from the subject; and identifying the subject as having elevated levels of Treg cells and NK cells compared to a reference level.

[0027] In some embodiments of any of the methods described herein, the reference level of Treg cells is the level of Treg cells in a population of healthy subjects.

[0028] In some embodiments of any of the methods described herein, the reference level of Treg cells is the 75% percentile of the median level of the number of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 80% percentile of the median level of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 85% percentile of the median level of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 90% percentile of the median level of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 95% percentile of the median level of Treg cells in a healthy patient population.

[0029] In some embodiments of any of the methods described herein, the reference level of NK cells is the level of NK cells in a population of healthy subjects.

[0030] In some embodiments of any of the methods described herein, the reference level of NK cells is the 75% percentile of the median level of the number of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 80% percentile of the median level of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 85% percentile of the median level of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 90% percentile of the median level of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 95% percentile of the median level of NK cells in a healthy patient population.

[0031] In some embodiments of any of the methods described herein, the cancer is a solid tumor.In certain embodiments of any of the methods described herein, the solid tumor is non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), small cell lung cancer (SCLC), head and neck cancer, or esophageal cancer.

[0032] In some embodiments of any of the methods described herein, the cancer is a hematological cancer.

[0033] Also provided herein are methods of treating a subject having cancer, comprising administering a therapeutically effective amount of an anti-CCR8 binding agent and a therapeutically effective amount of an anti-ILT4 binding agent to a subject previously identified or diagnosed as having cancer, and previously identified as having elevated levels of Treg cells, elevated levels of NK cells, and an increased number of M2 macrophages compared to reference levels.

[0034] Also provided herein are methods of selecting anti-CCR8 and anti-ILT4 binding agents for a subject previously identified or diagnosed as having cancer, and previously identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of NK cells compared to reference levels.

[0035] Also provided herein are methods of selecting a subject previously identified or diagnosed as having cancer, and previously identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of M2 macrophages compared to reference levels, for treatment with an anti-CCR8 binding agent and an anti-ILT4 binding agent.

[0036] Also provided herein is a method of predicting the efficacy of treatment with an anti-CCR8 binding agent and an anti-ILT4 binding agent in a subject in need thereof, comprising determining that a subject diagnosed or identified as having cancer and identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of M2 macrophages compared to reference levels is likely to have a positive therapeutic response to treatment with the pharmaceutical composition; or determining that a subject diagnosed or identified as having cancer and not identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of M2 macrophages compared to reference levels is unlikely to have a positive therapeutic response to treatment with the anti-CCR8 binding agent and an anti-ITL4 binding agent.

[0037] In some embodiments of any of the methods described herein, the anti-CCR8 binding agent is an anti-CCR8 antibody or antigen-binding fragment thereof (e.g., a depletion antibody or antigen-binding fragment thereof that has the ability to interfere with ligand binding to CCR8).

[0038] In some embodiments of any of the methods described herein, the anti-ILT4 binding agent is an anti-ILT4 antibody or antigen-binding fragment thereof (e.g., a blocking antibody that interferes with ILT4 / LILRB2 interaction with HLA-G molecules).

[0039] In some embodiments of any of the methods described herein, the method further comprises administering an immune checkpoint inhibitor to the subject. In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments of any of the methods described herein, the immune checkpoint inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0040] In some embodiments of any of the methods described herein, the method further includes measuring levels of Treg cells, NK cells, and M2 macrophages in a sample obtained from the subject; and identifying the subject as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of M2 macrophages compared to reference levels.

[0041] In some embodiments of any of the methods described herein, the reference level of Treg cells is the level of Treg cells in a population of healthy subjects.

[0042] In some embodiments of any of the methods described herein, the reference level of Treg cells is the 75% percentile of the median level of the number of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 80% percentile of the median level of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 85% percentile of the median level of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 90% percentile of the median level of Treg cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of Treg cells is the 95% percentile of the median level of Treg cells in a healthy patient population.

[0043] In some embodiments of any of the methods described herein, the reference level of NK cells is the level of NK cells in a population of healthy subjects.

[0044] In some embodiments of any of the methods described herein, the reference level of NK cells is the 75% percentile of the median level of the number of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 80% percentile of the median level of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 85% percentile of the median level of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 90% percentile of the median level of NK cells in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of NK cells is the 95% percentile of the median level of NK cells in a healthy patient population.

[0045] In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the level of M2 macrophages in a population of healthy subjects.

[0046] In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 75% percentile of the median level of M2 macrophages number in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 80% percentile of the median level of M2 macrophages in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 85% percentile of the median level of M2 macrophages in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 90% percentile of the median level of M2 macrophages in a healthy patient population. In some embodiments of any of the methods described herein, the reference level of M2 macrophages is the 95% percentile of the median level of M2 macrophages in a healthy patient population.

[0047] In some embodiments of any of the methods described herein, the cancer is a solid tumor. In certain embodiments of any of the methods described herein, the solid tumor is non-small cell lung cancer, hepatocellular carcinoma, small cell lung cancer, head and neck cancer, or esophageal cancer.

[0048] In some embodiments of any of the methods described herein, the cancer is a hematological cancer.

[0049] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Methods and materials are described herein for use in this invention; other suitable methods and materials known in the art can also be used.Materials, methods, and examples are illustrative only and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety.In case of conflict, the present specification, including definitions, will prevail.

[0050] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0051] [Figure 1] 1A-1B provide graphs showing the association between high levels of immunosuppressive M2 macrophages and limited PD(L)-1 responses in patients with small cell lung cancer (SCLC). FIG 1A is a graph showing a reanalysis of patient survival probability data. FIG 1B is a graph showing a reanalysis of patient heatmap data. [Diagram 2] 2A-2B provide graphs showing that SCLC patients with higher levels of M2 macrophages have a higher degree of ILT4 expression and fewer immune T cells. FIG. 2A is a graph showing ILT4 expression in M2 vs. non-M2 samples. FIG. 2B is a graph showing CD8 T cells, CD4-naive T cells, CD4-memory-resting T cells, and CD4-memory-activated T cells in M2-enriched samples. ****p<0.00001 [Diagram 3] FIG. 3 is a graph showing that immunosuppressive M2 macrophages are highly expressed in approximately 30% of non-small cell lung cancer (NSCLC) patients. [Figure 4]FIG. 4 is a schematic diagram showing repolarization of M2 (suppressive) macrophages into M1 (inflammatory) macrophages by anti-ILT4 antibodies. [Diagram 5] Figure 5 is a graph showing a reanalysis of heatmap data in NSCLC patients. Approximately 30% of patients had a high Treg signature, with population 1 having high Treg cells and high NK cells (Treg high NK high) and population 2 having high Treg cells and low NK cells (Treg high NK low). [Figure 6] FIG. 6 is a schematic diagram showing effective tumor killing by CCR8 antibody in the presence of Treg cells (left panel) and NK cells (right panel), which interfere with anti-PD(L)1 efficacy. [Figure 7] Figure 7 is a graph showing the patient populations that would benefit most from a new combination therapy involving ILT4 and CCR8 in combination with toripalimab. The graph shows the percentage of patients in each of the two identified populations that are likely to benefit from the combination therapy (i.e., the "Treg high, effector high" population and the "M2 enriched" population). Data is shown for hepatocellular carcinoma (HCC), NSCLC adenocarcinoma, SCLC, head and neck cancer, and esophageal cancer. M1 and M2 values ​​for SCLC are based on the ADAPTS:LM22 profile. Treg patterns are derived from GSVA using ranked LM22 profiles. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] Detailed Description The present disclosure provides a method for predicting the efficacy of a cancer therapeutic agent in a subject (e.g., a cancer patient). For example, the present disclosure provides a method for predicting the efficacy of an immune checkpoint inhibitor (ICI), an anti-CCR8 binding agent (e.g., an anti-CCR8 antibody, such as a depleting antibody), and / or an anti-ILT4 binding agent (e.g., an anti-ILT4 antibody, such as a blocking antibody) in a cancer patient. Also disclosed is a method for treating a subject (e.g., a patient) having one or more cancers with a cancer therapeutic agent. For example, the present disclosure provides a method for treating a subject having one or more cancers with an ICI, an anti-CCR8 binding agent, an anti-ILT4 binding agent, and / or any combination thereof.

[0053] Predicting the efficacy of cancer treatments Provided herein is a method of predicting the efficacy of treatment with a pharmaceutical composition comprising an immune checkpoint inhibitor in a subject in need thereof (e.g., a subject having any of the cancers described herein), the method comprising: determining that a subject diagnosed or identified as having cancer and identified as having a decreased level of M2 macrophages compared to a reference level is likely to have a positive therapeutic response to treatment with the pharmaceutical composition; or determining that a subject diagnosed or identified as having cancer and identified as having an increased level of M2 macrophages compared to a reference level is unlikely to have a positive therapeutic response to treatment with the pharmaceutical composition.

[0054] Also provided herein is a method of predicting the efficacy of treatment with a pharmaceutical composition comprising an anti-CCR8 binding agent in a subject in need thereof (e.g., a subject having any of the exemplary cancers described herein), comprising determining that a subject diagnosed or identified as having cancer and identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels is likely to have a positive therapeutic response to treatment with the pharmaceutical composition; or determining that a subject diagnosed or identified as having cancer and identified as having elevated levels of Treg cells and decreased levels of NK cells compared to reference levels is unlikely to have a positive therapeutic response to treatment with the pharmaceutical composition.

[0055] Also provided herein is a method of predicting the efficacy of treatment with an anti-CCR8 binding agent and an anti-ILT4 binding agent in a subject in need thereof (e.g., a subject having any of the exemplary cancers described herein), comprising determining that a subject diagnosed or identified as having cancer and identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of M2 macrophages compared to reference levels is likely to have a positive therapeutic response to treatment with the pharmaceutical composition; or determining that a subject diagnosed or identified as having cancer and not identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of M2 macrophages compared to reference levels is unlikely to have a positive therapeutic response to treatment with the anti-CCR8 binding agent and an anti-ITL4 binding agent.

[0056] M2 macrophages In contrast to classically activated macrophages (also known as M1 macrophages), M2 macrophages are alternatively activated. M2 macrophages are immunosuppressive in nature. Unlike inflammatory M1 macrophages, M2 macrophages tend to promote angiogenesis and neovascularization, as well as stromal activation and remodeling, thereby influencing the direction of cancer progression and negatively affecting patient prognosis. M1 macrophages are characterized by the expression of HLA-DR and CD197, while M2 highly expresses CD163, CD209, CD206, CCL2, etc. M2 macrophages have been described in more detail in the art. See, for example, Liu et al., Cancer Cell Int, 21:389, 2021; Tiainen et al., Histopathology, 66:873-83, 2015.

[0057] As used herein, the "reference level" of a parameter can refer to the level of that parameter in a healthy patient (e.g., a patient without autoimmune disorder, inflammatory disorder, or allergy) or the level of that parameter in a population of healthy subjects.For example, the "reference" level of M2 macrophages can refer to the level of M2 macrophages in a healthy patient (e.g., a patient without autoimmune disorder, inflammatory disorder, or allergy) or the level of M2 macrophages in a population of healthy subjects.In a specific example, the reference level of M2 macrophages is the 55% percentile, 60% percentile, 65% percentile, 70% percentile, 75% percentile, 80% percentile, 85% percentile, 90% percentile, or 95% percentile of the median level of the number of M2 macrophages in a healthy patient population.

[0058] Treg cells Regulatory T cells (Treg or Treg cells) play a crucial role in controlling tumor immunity as a key mechanism for controlling immune system homeostasis and the body's immune tolerance. Treg cells are CD4 T cells that induce reactivity against self-antigens and tumor-expressed antigens. + Helper T cells and CD8 + It can inhibit the activation and differentiation of cytotoxic T cells. In the tumor microenvironment (TME), Treg cells can be induced and differentiated by conventional T cells, which have strong immunosuppressive functions, inhibit antitumor immunity, and promote tumor initiation and development. Treg cells can also suppress the function of immune effector cells through various mechanisms, and are important factors in tumor immune escape. Forkhead / winged helix transcription factor (Foxp3) is specifically expressed in Treg cells and is currently thought to be involved in the activation and differentiation of CD4 + CD25 + Foxp3 + is considered to be a classical composite marker of Treg cells. In fact, Foxp3, in addition to its ability to label Treg cells, predominantly controls the function of Treg cells, and only when Foxp3 is continuously expressed, can it be ensured that the suppressive ability of Treg cells is maintained in an intact state. Treg cells are described in more detail in the art. See, for example, Li et al., Mol Cancer, 19:116, 2020; Nishikawa and Sakaguchi, Curr Opin Immunol, 27:1-7, 2014.

[0059] As used herein, the "reference level" of Treg cells can refer to the level of Treg cells in healthy patients (e.g., patients without autoimmune disorder, inflammatory disorder, or allergy), or the level of Treg cells in a population of healthy subjects.In a specific example, the reference level of Treg cells is the 55% percentile, 60% percentile, 65% percentile, 70% percentile, 75% percentile, 80% percentile, 85% percentile, 90% percentile, or 95% percentile of the median level of the number of Treg cells in a population of healthy patients.

[0060] NK cells Natural killer (NK) cells are lymphocytes that have the innate ability to lyse tumor cells without the need for prior sensitization. NK cells can induce the death of target cells by releasing cytotoxic granules containing granzymes and perforin, and by death receptor-mediated pathways (e.g., FasL / Fas). NK cells also perform immunoregulatory functions by secreting chemokines and cytokines, such as RANTES and IFN-γ. In humans, NK cells are traditionally identified based on the absence of CD3 and the presence of CD56 on their surface, characterized by flow cytometry. NK cells have been described in more detail in the art. See, e.g., Liu et al., J Hematol Oncol, 14:7, 2021; Freud et al., Immunity, 47(5):820-833, 2017; Spits et al., Nat Rev Immunol, 13(2):145-9, 2013. NK cells also have Fc receptors that are important for binding to the Fc region of therapeutic antibodies, resulting in activation and degranulation of NK cells for effective killing of target cells.

[0061] As used herein, a "reference level" of NK cells can refer to the level of NK cells in a healthy patient (e.g., a patient without an autoimmune disorder, inflammatory disorder, or allergy) or the level of NK cells in a population of healthy subjects. In certain examples, the reference level of NK cells is the 55% percentile, 60% percentile, 65% percentile, 70% percentile, 75% percentile, 80% percentile, 85% percentile, 90% percentile, or 95% percentile of the median level of the number of NK cells in a population of healthy patients.

[0062] Immune checkpoint inhibitors ICI is a new class of immunotherapeutic drugs that has improved the treatment of a wide range of cancers, such as metastatic melanoma, non-small lung cancer, or renal cell carcinoma. ICI can include humanized and human monoclonal antibodies that target inhibitory receptors (e.g., CTLA-4, PD-1, LAG-3, TIM-3) and ligands (e.g., PD-L1) expressed on T lymphocytes, antigen-presenting cells, and tumor cells, and elicit anti-tumor responses by stimulating the immune system. For example, the ICI described herein can be an anti-PD-1 antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and / or an anti-CTLA-4 antibody or its antigen-binding fragment.

[0063] A summary of various ICIs, including corresponding immune checkpoints, targeted indications (e.g., tumor types targeted by each ICI), and clinical trials (if any) is provided in Table 1. Further details regarding ICIs can be found in the art. For example, see Franzin et al., Front Immunol, 11:574271, 2020; Johnson et al., Nat Rev Clin Oncol, 19: 254-267, 2022.

[0064] Table 1. Overview of major ICIs, targeted tumors, and clinical trials TIFF2025512837000002.tif36149TIFF2025512837000003.tif221149TIFF20255128370 00004.tif216149TIFF2025512837000005.tif221149TIFF2025512837000006.tif61149

[0065] Anti-CCR8 binding substance The anti-CCR8 binding agent can be an agent that specifically binds to chemokine (CC motif) receptor 8 (CCR8). For example, the anti-CCR8 binding agent can be an anti-CCR8 antibody or a fragment thereof. As used herein, the term "antibody" refers to the broadest sense and specifically encompasses various embodiments, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), and antibody fragments, such as diabodies, so long as they exhibit the desired biological activity. Antibodies are primarily amino acid-based molecules, but may also include one or more modifications, including but not limited to the addition of one or more detectable labels. In some embodiments, the anti-CCR8 binding agent (e.g., anti-CCR8 antibody) can be a depleting antibody. In certain embodiments, the depleting antibody can have the ability to prevent ligands from binding to CCR8. In certain instances, non-fucosylated anti-CCR8 antibodies can be used, which have increased antibody-dependent cellular cytotoxicity (ADCC) activity and thus are agents that successfully deplete Tregs that express CCR8.

[0066] In some examples, BMS-986340 can be used as an anti-CCR8 binding agent (e.g., anti-CCR8 antibody) in the methods of the present disclosure. BMS-986340 is a newly developed anti-CCR8 mAb that significantly reduces CCR8+ Treg in human tumor explants. Other anti-CCR8 antibodies for use in the methods of the present disclosure have been described in the art. See, for example, Campbell et al., Cancer Res, 81 (11): 2983-2994, 2021.

[0067] Anti-ILT4 binding substance The anti-ILT4 binding agent can be an agent that specifically binds to the inhibitory immune checkpoint receptor immunoglobulin-like transcript 4 (ILT4); leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2); lymphocyte immunoglobulin-like receptor 2 (LIR2); monocyte / macrophage immunoglobulin-like receptor 10 (MIR-10); CD85d. For example, the anti-ILT4 binding agent can be an anti-ILT4 antibody or a fragment thereof. In some embodiments, the anti-ILT4 binding agent (e.g., an anti-ILT4 antibody) can be a blocking antibody. In certain embodiments, the blocking antibody can inhibit the interaction of ILT4 (LILRB2) with its ligands, including HLA-G.

[0068] In some examples, MK-4830 can be used as an anti-ILT4 binding agent (e.g., an anti-ILT4 antibody) in the methods of the present disclosure. MK-4830 is a human monoclonal antibody against ILT4 with potential immunomodulatory and anti-neoplastic activity. Other anti-ILT4 antibodies for use in the methods of the present disclosure have been described in the art. See, for example, Chen et al., Theranostics 11(7):3392-3416, 2021.

[0069] Treatment Provided herein are methods of treating a subject having cancer (e.g., any of the exemplary cancers described herein), comprising administering a therapeutically effective amount of an immune checkpoint inhibitor to a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having an elevated level of M2 macrophages compared to a reference level (e.g., any of the exemplary reference levels described herein).

[0070] Also provided herein is a method of treating a subject having cancer (e.g., any of the exemplary cancers described herein), comprising administering a therapeutically effective amount of an anti-ILT4 binding agent to a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of M2 macrophages compared to a reference level (e.g., any of the exemplary reference levels described herein).

[0071] Also provided herein are methods of treating a subject having cancer (e.g., any of the exemplary cancers described herein), comprising administering a therapeutically effective amount of an anti-CCR8 binding agent to a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels (e.g., any of the exemplary reference levels described herein).

[0072] Also provided herein are methods of treating a subject having cancer (e.g., any of the exemplary cancers described herein), comprising administering a therapeutically effective amount of an anti-CCR8 binding agent and a therapeutically effective amount of an anti-ILT4 binding agent to a subject previously identified or diagnosed as having cancer, and previously identified as having elevated levels of Treg cells, elevated levels of NK cells, and an increased number of M2 macrophages compared to reference levels (e.g., any of the exemplary reference levels described herein).

[0073] As used herein, "treating" or "treatment" means alleviating, ameliorating, relieving, delaying the onset of, inhibiting the progression of, reducing the severity of, and / or reducing the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. For example, "treating" cancer can mean extending the survival of a subject diagnosed or identified as having cancer. Additionally or alternatively, "treating" cancer can mean inhibiting the growth and / or spread of cancer or tumors.

[0074] As used herein, the term "subject" refers to any organism to which the method of the present disclosure can be applied, for example, for experimental and / or therapeutic purposes. Typical subjects include animals such as mammals (e.g., mice, rats, rabbits, dogs, pigs, non-human primates, and humans). In some examples, "subject" can refer to cancer patients, for example, patients diagnosed and / or identified as having cancer.

[0075] The cancers that the treatment method of the present invention is useful for can include any malignant cell type, such as those found in solid tumors or blood tumors.Exemplary solid tumors can include, but are not limited to, tumors of organs selected from the group consisting of pancreas, colon, appendix, stomach, brain, head, neck, ovary, kidney, larynx, sarcoma, lung (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), bladder, melanoma, prostate, and breast.Exemplary blood tumors include bone marrow tumors, T-cell or B-cell malignancies, leukemia, lymphoma, blastoma, and myeloma, etc. Other examples of cancers that may be treated using the methods provided herein include, but are not limited to, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, gastric or stomach cancer (including gastrointestinal and gastrointestinal stromal cancer), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, various types of head and neck cancer, and melanoma.

[0076] In certain embodiments, the cancers treated according to the methods described herein include, but are not limited to, prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bronchial cancer, bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, uterine or endometrial cancer, oral or pharyngeal cancer, non-Hodgkin's lymphoma, thyroid cancer, kidney cancer, biliary tract cancer, small intestine or appendix cancer, salivary gland cancer, thyroid cancer, adrenal cancer, squamous cell carcinoma, mesothelioma, bone cancer, thymoma / thymic carcinoma, glioblastoma, myelodysplastic syndrome, soft tissue sarcoma, DIPG, adenocarcinoma, osteosarcoma, chondrosarcoma, leukemia, or pancreatic cancer. In some embodiments, the cancers treated according to the methods described herein include carcinoma (e.g., adenocarcinoma), lymphoma, blastoma, melanoma, sarcoma, or leukemia. In certain embodiments, cancers treated according to the methods described herein include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer (e.g., hepatoma and hepatoma), bladder cancer, breast cancer, inflammatory breast cancer, Merkel cell carcinoma, colon cancer, colorectal cancer, gastric cancer, bladder cancer, endometrial cancer, myeloma (e.g., multiple myeloma), salivary gland, cancer, kidney cancer (e.g., renal cell carcinoma and Wilms' tumor), basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, serous adenocarcinoma, or various types of head and neck cancer. In certain embodiments, the cancers treated according to the methods described herein include desmoplastic melanoma, inflammatory breast cancer, thymoma, rectal cancer, anal cancer, or surgically treatable or non-surgically treatable brain stem glioma.In some examples, the cancers treated according to the methods described herein include adrenocortical carcinoma, bladder urothelial carcinoma, glioblastoma multiforme, low-grade glioma, cervical cancer and endocervical cancer, colon adenocarcinoma, colorectal adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, small cell lung carcinoma, ovarian serous adenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, skin melanoma, gastric adenocarcinoma, thyroid carcinoma, and / or uterine endometrial carcinoma.

[0077] Methods for selecting a treatment for a subject Also provided herein is a method of selecting a pharmaceutical composition comprising an immune checkpoint inhibitor for a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having a reduced level of M2 macrophages compared to a reference level (e.g., any of the exemplary reference levels described herein).

[0078] Also provided herein is a method of selecting a pharmaceutical composition comprising an anti-ILT4 binding agent for a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of M2 macrophages compared to a reference level (e.g., any of the exemplary reference levels described herein).

[0079] Also provided herein are methods of selecting a pharmaceutical composition comprising an anti-CCR8 binding agent for a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels (e.g., any of the exemplary reference levels described herein).

[0080] Also provided herein are methods of selecting anti-CCR8 and anti-ILT4 binding agents for a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of NK cells compared to a reference level (e.g., any of the exemplary reference levels described herein).

[0081] Methods for selecting subjects for treatment Also provided herein is a method of selecting a subject previously identified or diagnosed with cancer (e.g., any of the exemplary cancers described herein) and previously identified as having a reduced level of M2 macrophages compared to a reference level (e.g., any of the exemplary reference levels described herein) for treatment with a pharmaceutical composition comprising an immune checkpoint inhibitor.

[0082] Also provided herein is a method of selecting a subject previously identified or diagnosed as having a cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of M2 macrophages compared to a reference level (e.g., any of the exemplary reference levels described herein) for treatment with a pharmaceutical composition comprising an anti-ILT4 binding agent.

[0083] Also provided herein are methods of selecting a subject previously identified or diagnosed as having cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of Treg cells and elevated levels of NK cells compared to reference levels (e.g., any of the exemplary reference levels described herein), for treatment with a pharmaceutical composition comprising an anti-CCR8 binding agent.

[0084] Also provided herein are methods of selecting a subject previously identified or diagnosed as having a cancer (e.g., any of the exemplary cancers described herein) and previously identified as having elevated levels of Treg cells, elevated levels of NK cells, and elevated levels of M2 macrophages compared to reference levels (e.g., any of the exemplary reference levels described herein) for treatment with an anti-CCR8 binding agent and an anti-ILT4 binding agent. EXAMPLES

[0085] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0086] Example 1. Translating transcriptomics data into immune cells We wanted to find bioinformatics insights from existing databases so that data related to past failures could guide future success in immuno-oncology. To this end, we evaluated survival curves to identify patterns. We analyzed cancer omics data and transformed genomics data into actionable insights. Existing omics data from large and small public and private databases were analyzed and gene expression was expressed into immune cell subtypes. Heat maps were also evaluated to understand the response or lack thereof. Specifically, the leukocyte gene signature matrix (LM22) with 547 genes was used by the CIBERSORT algorithm to calculate gene weights for each cell type. This was then validated in 3000 human transcriptomes. The open source ADAPTS (Automatic Deconvolution Enhancement of Tissue-Specific Cellular Profiles) software was used to calculate immune cell expansion using the LM22 matrix. See, for example, cran.r-project.org / web / packages / ADAPTS / index.html. The genes ranked from LM22 were also used in gene set variation analysis (GSVA). This approach was validated using cells sorted from early stage non-small cell lung cancer (NSCLC) and follicular lymphoma patients. We were able to improve the efficiency of the analysis approach and use these insights to prioritize combinations.

[0087] Example 2 The tumor microenvironment limits how much benefit patients receive from PD-1 inhibitors Publicly available data from "The Cancer Genome Atlas" (TCGA) and other sources were analyzed to identify patterns associated with patient non-response to PD-1 blockade. For example, we analyzed data from Ayers et al., 2017 (J Clin Invest, 127(8):2930-2940), which shows progression-free survival (PFS) duration in 244 patients treated with the PD-1 inhibitor KEYTRUDA versus T-cell infiltrating gene expression profile (GEP) score. A pattern of lack of objective response was generally observed in patients whose tumors showed low expression levels across these genes, presumably representing tumors without a T-cell infiltrating phenotype. Patients whose tumors had lower T-cell infiltrating GEP scores (e.g., less than -0.3) usually showed rapid disease progression, whereas variable progression durations were observed with higher T-cell infiltrating GEP scores. A large proportion of patients were identified as having additional immunosuppressive mechanisms that could impede tumor killing by T cells, and the poor prognosis in these patients was likely caused by undesirable immunosuppressive mechanisms in the tumor microenvironment (TME). Overall, this analysis uncovers novel immunosuppressive mechanisms in the TME.

[0088] Example 3 Changing an unfavorable TME to a favorable TME for anti-PD-1 treatment response As described in Example 2, our analysis of cancer omics data revealed novel immunosuppressive mechanisms in the TME. Given the role of the TME in limiting therapeutic response to PD-1 inhibitors, we aimed to modify the TME unfavorable for anti-PD-1 therapeutic response to a favorable TME. To this end, transcriptomics data of cancer patients were converted to immune cell types using a modified algorithm containing 30-45 genes. We then identified a group of cancer patients (e.g., NSCLC / SCLC) with locatable dominant MOA. We then identified targets based on biology to develop best-in-class drug candidates. This approach appears to elucidate key immunosuppressive mechanisms and may address "immune escape." Additionally, drug combinations appear to address unfavorable TMEs and provide better outcomes for patients.

[0089] Example 4 High levels of immunosuppressive macrophages may be the reason for limited PD(L)-1 responses in SCLC patients Cancer omics data from small cell lung cancer (SCLC) patients was reanalyzed to identify patterns associated with limited patient response to PD(L)-1 therapy. Specifically, survival plot and heat map data from George et al., 2015 (Nature, 524(7563): 47-53 (2015)) were reanalyzed using the methods described in the previous examples. The results are depicted in Figure 1A and Figure 1B. As shown in Figure 1A and 1B, patients with increased M1 macrophages (i.e., patients with higher levels of M1 macrophages; high M1 (M1 enriched)) showed higher survival probability compared to patients with higher levels of immunosuppressive M2 macrophages (high M2 (M2 enriched)). Analysis of profiles with elevated levels of resting dendritic cells (DCs) and M2 macrophages showed that approximately 30% of SCLC patients had a high M2 (i.e., immunosuppressive macrophage) signature and had a poorer prognosis. Thus, our analysis indicated that high levels of immunosuppressive macrophages in SCLC may be the reason for the limited PD(L)-1 response in SCLC patients.

[0090] Example 5: High M2 SCLC patients have higher ILT4 expression and fewer immune T cells Furthermore, reanalysis of data obtained from SCLC patients showed that ILT4 expression was significantly higher and immune T cells were fewer in SCLC patients with high M2 (i.e., high levels of immunosuppressive M2 macrophages). The results are described in Figure 2A and Figure 2B. Specifically, ILT4 expression was found to be significantly higher in M2 samples compared to non-M2 samples (Figure 2A). Also, M2-enriched samples were found to have fewer immune T cells (Figure 2B).

[0091] Example 6 NSCLC patients with high levels of M2 macrophages are less likely to respond to PD(L)-1 therapy Next, the public data of non-small cell lung cancer (NSCLC) patients was reanalyzed to identify patterns associated with limited response of NSCLC patients to PD(L)-1 therapy. Specifically, the data published by The Cancer Genome Atlas was reanalyzed using the method described in the previous example. The results are shown in Figure 3. As shown in Figure 3, high expression of immunosuppressive M2 macrophages was found in about 30% of patients. Thus, our analysis showed that NSCLC patients with high levels of M2 macrophages are more likely to not respond to PD(L)-1 therapy.

[0092] Based on the knowledge learned from the above examples, the inventors were able to rationally develop anti-ILT4 antibodies with the intention of repolarizing M2 (immunosuppressive) macrophages to M1 (inflammatory) macrophages. A schematic diagram showing the repolarization of M2 (suppressive) macrophages to M1 (inflammatory) macrophages by anti-ILT4 antibodies is depicted in Figure 4.

[0093] Example 7 NSCLC patients with a Treg signature could benefit from anti-CCR8 depleting antibody therapy in combination with toripalimab Reanalysis of NSCLC patient data also showed that approximately 30% of NSCLC patients have a high Treg signature and these patients may benefit from the combination of anti-CCR8 depleting antibody and toripalimab. The results are described in Figure 5. As illustrated in Figure 5, high levels of regulatory T cells (Treg) were found in patients who were unlikely to benefit from PD-1 therapy. Of these, some patients had high Treg and high NK cells (population 1; Treg 高 N.K. 高 ), whereas other patients had high Treg and low NK cells (population 2; Treg 高 N.K. 低 The Treg high population generally appeared to be distinct from the M2 high group (described in the previous example). 高 N.K. 低The likelihood of benefiting patients is low due to the low number of NK cells present (i.e., CCRR-8 therapy can benefit these patients, but only if NK cells are present), whereas patients with high levels of Treg and NK cells (i.e., Treg 高 N.K. 高 Patients) are likely to benefit substantially from the combination of toripalimab and anti-CCR8 or a similar combination treatment regimen.

[0094] This analysis shows that depleting immunosuppressive Tregs allows cytotoxic T cells to efficiently kill tumors. Specifically, the presence of Treg cells can interfere with the efficacy of anti-PD(L)1, and anti-CCR8 and effector NK cells are required for effective Treg depletion. Thus, effective tumor killing can be achieved using CCR8 antibodies in the presence of NK cells. A schematic of this concept is shown in Figure 6.

[0095] Example 8 Patient Populations Benefiting from Combination Therapy Reanalysis of patient data (described in the previous examples) identified patient populations that are likely to benefit from the combination therapy proposed above. Specifically, our analysis identified Treg-high effector-high and M2-rich populations as patient populations that would most likely benefit from a therapy that includes ILT4 and CCR8 in combination with toripalimab. The results are described in Figure 7 and Table 2 below. The graph in Figure 7 shows the percentage of patients in each of the two identified populations (i.e., the "Treg-high, effector-high" and "M2-rich" populations) that are likely to benefit from the combination therapy. Data is shown for hepatocellular carcinoma (HCC), NSCLC adenocarcinoma, SCLC, head and neck cancer, and esophageal cancer. M1 and M2 values ​​for SCLC are based on the ADAPTS:LM22 profile. Treg patterns are obtained from GSVA using ranked LM22 profiles. Given the limited overlap of patients in these two categories, CCR8 and anti-ILT4 antibody therapy may have the potential to benefit most tumor patients.

[0096] Table 2. Patient populations likely to benefit from combination therapy TIFF2025512837000007.tif202149

[0097] Other Aspects Although the present invention has been described in conjunction with the detailed description thereof, it should be understood that the foregoing description is intended to illustrate, and not to limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A composition comprising a therapeutically effective amount of an immune checkpoint inhibitor for use in a method of treating a subject previously identified or diagnosed with cancer and previously identified as having reduced levels of M2 macrophages compared to a reference level.

2. The composition according to claim 1, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or its antigen-binding fragment.

3. The composition according to claim 1, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment.

4. The method described above, A step of measuring the level of M2 macrophages in samples previously obtained from the subject; and The step of identifying a subject that has a reduced level of M2 macrophages compared to a reference level. The composition according to claim 1, further comprising:

5. A composition comprising a therapeutically effective amount of an anti-ILT4 conjugate for use in a method of treating a subject previously identified or diagnosed with cancer and previously identified as having elevated levels of M2 macrophages compared to a reference level.

6. The composition according to claim 5, wherein the anti-ILT4 binding substance is an anti-ILT4 antibody or an antigen-binding fragment thereof.

7. The composition according to claim 5, further comprising the step of administering an immune checkpoint inhibitor to the subject.

8. The composition according to claim 7, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof.

9. The composition according to claim 7, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment.

10. The method described above, The step of measuring the level of M2 macrophages in the sample obtained from the subject; and The step of identifying a subject that has an elevated level of M2 macrophages compared to a reference level. The composition according to claim 5, further comprising:

11. The composition according to any one of claims 1 to 10, wherein the M2 macrophages have an elevated level of ILT4 expression compared to a reference level.

12. The composition according to claim 11, wherein the reference level of M2 macrophages is the level of M2 macrophages in a population of healthy subjects.

13. The composition according to claim 11, wherein the reference level of M2 macrophages is the 75th percentile of the median number of M2 macrophages in a healthy patient population.

14. The composition according to claim 11, wherein the reference level of M2 macrophages is the 80th percentile of the median level of M2 macrophages in a healthy patient population.

15. The composition according to claim 11, wherein the reference level of M2 macrophages is the 85th percentile of the median level of M2 macrophages in a healthy patient population.

16. The composition according to claim 11, wherein the reference level of M2 macrophages is the 90th percentile of the median level of M2 macrophages in a healthy patient population.

17. The composition according to claim 11, wherein the reference level of M2 macrophages is the 95th percentile of the median level of M2 macrophages in a healthy patient population.

18. The composition according to any one of claims 1 to 10, wherein the cancer is a solid tumor.

19. The composition according to claim 18, wherein the solid tumor is non-small cell lung cancer, hepatocellular carcinoma, small cell lung cancer, head and neck cancer, or esophageal cancer.

20. The composition according to any one of claims 1 to 10, wherein the cancer is a blood cancer.

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