Selection of patients for combination therapy

Abstract

To provide methods of selecting cancer patients for treatment with a combination therapy comprising an HDAC inhibitor and a second therapeutic agent.SOLUTION: In particular, methods are provided for examination of a non-cancer cell type, which is CD14-positive, HLA-DR-high and / or CD16-negative, as a therapeutic indicator in the setting of HDAC inhibitor combination therapies.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 668,055, filed May 7, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Background technology]

[0003] background Cancer, tumors, tumor-related disorders, and neoplastic disease conditions are serious and often life-threatening. These diseases and disorders are characterized by rapidly proliferating cell proliferation and remain the subject of research efforts aimed at identifying therapeutic agents that are effective in treating them. Such agents prolong patient survival, inhibit the rapidly proliferating cell proliferation associated with neoplasms, or cause the regression of neoplasms.

[0004] HDAC inhibitors (HDACi) are an emerging class of therapeutic agents that promote differentiation and apoptosis in hematological and solid malignancies through chromatin remodeling and gene expression regulation. Although the antitumor effects of HDACi have been investigated, the impact of HDACi on systemic immunity in cancer patients remains unclear.

[0005] Cancer immunotherapy is needed in a variety of indications, such as non-small cell lung cancer, melanoma, etc. Accordingly, there is a great need in the art for effective compounds, compositions, and methods useful for treating cancer, either alone or in conjunction with other therapies used to treat these diseases or conditions. The present invention is directed to meeting this need.

[0006] overview In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0007] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0008] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer and who has progressed during and / or been deemed unresponsive to a prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0009] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma, and who has progressed during and / or been deemed unresponsive to a prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0010] In one embodiment, provided herein is a method of providing a prognosis for cancer in a patient, the method comprising: providing a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0011] In one embodiment, provided herein is a method of providing a prognosis for cancer in a patient, the method comprising: providing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0012] In one embodiment, provided herein is a method of providing a prognosis for cancer in a patient, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer and who has progressed during and / or been deemed unresponsive to prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0013] In one embodiment, provided herein is a method for providing a prognosis for cancer in a patient, the method comprising: preparing a peripheral blood sample from the patient diagnosed with non-small cell lung cancer and / or melanoma and who has progressed during and / or been deemed unresponsive to prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than a predetermined percentage.

[0014] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than approximately at least 5%, such as approximately at least 20%.

[0015] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than approximately at least 5%, such as approximately at least 20%.

[0016] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer and who has progressed during and / or been deemed unresponsive to a prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than approximately at least 5%, such as approximately at least 20%.

[0017] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma, and who has progressed during and / or been deemed unresponsive to a prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than approximately at least 5%, such as approximately at least 20%.

[0018] In one embodiment, provided herein is a method of providing a prognosis for cancer in a patient, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0019] In one embodiment, provided herein is a method of providing a prognosis for cancer in a patient, the method comprising: providing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than approximately at least 5%, such as approximately at least 20%.

[0020] In one embodiment, provided herein is a method of providing a prognosis for cancer in a patient, the method comprising: preparing a peripheral blood sample from the patient who has been diagnosed with cancer and / or who has progressed during and / or who has been deemed unresponsive to prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than approximately at least 5%, such as approximately at least 20%.

[0021] In one embodiment, provided herein is a method of providing a prognosis for cancer in a patient, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma, and who has progressed during and / or been deemed unresponsive to prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering a combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to total viable peripheral blood mononuclear cells is greater than approximately at least 5%, such as approximately at least 20%.

[0022] As such, provided herein in one embodiment is a method of selecting a patient for combination therapy comprising entinostat and a second therapeutic agent, the method comprising: providing a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0023] As such, provided herein in one embodiment is a method for selecting a patient for combination therapy comprising entinostat and a second therapeutic agent, the method comprising: providing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0024] In one embodiment, provided herein is a method of selecting a patient for combination therapy comprising entinostat and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer and who has worsened during and / or been deemed unresponsive to a prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0025] In one embodiment, provided herein is a method of selecting a patient for combination therapy comprising entinostat and a second therapeutic agent, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma, and who has progressed during and / or been deemed unresponsive to a prior therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0026] As such, provided herein in one embodiment is a method of selecting a patient for combination therapy comprising entinostat and an anti-PD-1 antibody, the method comprising: providing a peripheral blood sample from the patient diagnosed with cancer; enumerating the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0027] As such, provided herein in one embodiment is a method of selecting a patient for combination therapy comprising entinostat and an anti-PD-1 antibody, the method comprising: providing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma; enumerating the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0028] As such, provided herein in one embodiment is a method of selecting a patient for combination therapy comprising entinostat and an anti-PD-1 antibody, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer and who has progressed during and / or been deemed non-responsive to prior therapy; enumerating the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0029] As such, provided herein in one embodiment is a method of selecting a patient for combination therapy comprising entinostat and an anti-PD-1 antibody, the method comprising: preparing a peripheral blood sample from the patient diagnosed with cancer, e.g., non-small cell lung cancer and / or melanoma, and who has progressed during and / or been deemed non-responsive to prior therapy; enumerating the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells to viable peripheral blood mononuclear cells is greater than about at least 5%, such as about at least 20%.

[0030] In some embodiments, the anti-PD-1 antibody, anti-PD-L1 and / or CTLA4 blocking therapy, and HDAC inhibitor are administered in temporal proximity to treat cancer. In some embodiments, the present disclosure provides synergistic compositions of an anti-PD-1 antibody, anti-PD-L1 and / or CTLA4 blocking therapy, and HDAC inhibitor, wherein the anti-PD-1 antibody, anti-PD-L1 antibody and / or CTLA4 blocking therapy, and HDAC inhibitor contact each other within the human body (e.g., only within the human body).

[0031] In some embodiments, the disclosure provides methods of preparing a composition by contacting an anti-PD-1 antibody, an anti-PD-L1 and / or CTLA4 blocking therapy, and an HDAC inhibitor with each other at one location. [Brief explanation of the drawings]

[0032] [Figure 1]Figure 1 illustrates the percentage of CD14+HLA-DRHiCD16- monocytic cells relative to total viable PBMCs in blood samples obtained from pre-treated donors grouped into one of three categories: healthy donors (HD), NSCLC patients who respond to combination therapy (responders), and NSCLC patients who do not respond to combination therapy (non-responders), and shows the predictive and prognostic significance of baseline, pre-treatment CD14+HLA-DRHiCD16 cells relative to total peripheral blood mononuclear cells.

[0033] [Figure 2] Figure 2 illustrates the percentage of CD14+HLA-DRHiCD16- monocytic cells relative to total viable PBMCs in blood samples obtained from pre-treated donors grouped into one of three categories: (1) healthy donors (HD), (2) NSCLC patients with an objective response (complete response (CR) or partial response (PR)) to combination therapy in combination with patients with a treatment duration (TOT) of ≥ 16 weeks, and (3) progressive disease (PD) in combination with patients with a treatment duration of < 16 weeks, and shows the predictive and prognostic significance of baseline, percentage of pre-treatment CD14+HLA-DRHiCD16 cells relative to total peripheral blood mononuclear cells.

[0034] [Figure 3] Figure 2 illustrates the percentage of CD14+HLA-DRHiCD16- monocytic cells relative to total viable PBMCs in blood samples obtained from pre-treated donors grouped into one of three categories: (1) healthy donors (HD), (2) NSCLC patients with an objective response (complete response (CR) or partial response (PR)) to combination therapy in combination with patients with a treatment duration (TOT) of ≥ 24 weeks, and (3) progressive disease (PD) in combination with patients with a treatment duration of < 24 weeks, and shows the predictive and prognostic significance of baseline, percentage of pre-treatment CD14+HLA-DRHiCD16 cells relative to total peripheral blood mononuclear cells.

[0035] [Figure 4] Figure 4 illustrates the percentage of NSCLC patients who remained progression-free (progression-free survival (PFS)) at specific time intervals. Patients were grouped according to their baseline CD14+HLA-DRHiCD16- monocyte cell percentage relative to total peripheral blood mononuclear cells, which was above / equal to or below the calculated monocyte percentage midpoint of 13.1% of total peripheral blood mononuclear cells.

[0036] [Figure 5] Figure 5 illustrates the percentage of CD14+HLA-DRHiCD16- monocytic cells relative to total viable PBMCs in blood samples obtained from donors on day 1 of the first cycle of treatment (C1D1) grouped into one of three categories: healthy donors (HD), melanoma patients who respond to combination therapy (C1D1 responders), and melanoma patients who do not respond to combination therapy (C1D1 non-responders), showing the predictive and prognostic significance with respect to baseline, percentage of pre-treatment CD14+HLA-DRHiCD16 cells relative to total peripheral blood mononuclear cells.

[0037] [Figure 6] Figure 6 illustrates the percentage of NSCLC patients who remained progression-free (progression-free survival (PFS)) at specific time intervals. Patients were grouped according to their baseline CD14+HLA-DRHiCD16- monocyte cell percentage relative to total peripheral blood mononuclear cells, which fell above / equal to or below the midpoint of the calculated monocyte percentage of total surviving peripheral blood mononuclear cells of 9%. The data show that patients with high levels of monocytes at baseline experienced significantly longer PFS benefit from combination therapy.

[0038] [Figure 7]Figure 7 illustrates the percentage of CD14+HLA-DRHiCD16- monocytic cells relative to total viable PBMCs in blood samples obtained from pre-treated donors grouped into one of three categories: (1) healthy donors, (2) NSCLC patients responding to combination therapy, and (3) non-responders, and shows the predictive and prognostic significance of baseline, percentage of pre-treatment CD14+HLA-DRHiCD16 cells relative to total peripheral blood mononuclear cells.

[0039] [Figure 8] Figure 8 illustrates patients who had high monocytes, low monocytes, confirmed partial remissions, or stable disease during the study, demonstrating that responders with high baseline monocytes also experienced enhanced durability. DETAILED DESCRIPTION OF THE INVENTION

[0040] Detailed Description The conventional approach to select cancer patients for combination therapy relies on cancer assessment by histology or molecular analysis.The present disclosure provides a method that relies on the level of CD14 positive, HLA-DR high, and / or CD16 negative peripheral blood mononuclear cells in biological samples obtained from cancer patients as a predictive and prognostic biomarker for selecting patients for combination therapy with HDAC inhibitors and a second therapeutic agent.

[0041] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: obtaining a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is greater than 5%-40%.

[0042] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: obtaining a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is greater than 5%.

[0043] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: obtaining a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is greater than 10%.

[0044] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: obtaining a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is greater than 15%.

[0045] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: obtaining a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is greater than 20%.

[0046] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: obtaining a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is greater than about 25%.

[0047] In one embodiment, provided herein is a method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, the method comprising: obtaining a peripheral blood sample from the patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; counting the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is greater than about 30%.

[0048] In some embodiments, the peripheral blood sample is treated with an anticoagulant.

[0049] In some embodiments, the patient diagnosed with cancer has received prior treatment. In some embodiments, the patient diagnosed with cancer has received prior treatment and has progressed. In some embodiments, the patient diagnosed with cancer has received prior treatment and has been found to be non-responsive. In some embodiments, the prior treatment is selected from anti-PD-1, anti-PD-L1, and CTLA4 blocking treatment. In some embodiments, the patient diagnosed with cancer was treatment naive.

[0050] In some embodiments, measuring the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in a peripheral blood sample is performed by flow cytometry. In some embodiments, the peripheral blood mononuclear cell population is identified by cell surface markers. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total PBMCs is at least about 1% to 100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total PBMCs is at least about 5% to 100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total PBMCs is at least about 10% to 100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total PBMCs is at least about 15% to 100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is at least about 20%-100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is at least about 25%-100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is at least about 30%-100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is at least about 35%-100%. In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells is 40%-100%.

[0051] In some embodiments, the HDAC inhibitor is entinostat. In some embodiments, the HDAC inhibitor is vorinostat (SAHA). In some embodiments, the HDAC inhibitor is valproic acid. In some embodiments, the HDAC inhibitor is selected from belinstat (PXD101), LAQ824, panobinostat (LBH589), CI994, chidamide (HBI-8000; Epidaza®), and mocetinostat (MGCD0103).

[0052] In some embodiments, the HDAC inhibitor is administered orally. In some embodiments, the HDAC inhibitor is administered initially. In some embodiments, the HDAC inhibitor is administered weekly. In some embodiments, the HDAC inhibitor is administered every two weeks.

[0053] In some embodiments, the second therapeutic agent is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer, squamous cell carcinoma, or large cell carcinoma. In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is metastatic melanoma.

[0054] In some embodiments, the second therapeutic agent is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MPDL3280A. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the second therapeutic agent is MPDL3280A and the breast cancer is triple-negative breast cancer.

[0055] In some embodiments, the anti-PD-1 antibody or the anti-PD-L1 antibody is administered by infusion.

[0056] In some embodiments, the second therapeutic agent is a CTLA4 blocking agent. In some embodiments, the CTLA4 blocking agent is ipilimumab. In some embodiments, the CTLA4 blocking agent is tremelimumab.

[0057] To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0058] As used herein, "progression" refers to a disease, such as cancer, that is getting worse or spreading throughout the body.

[0059] As used herein, the phrases "unresponsive" and "failed to respond" refer to a patient or condition that has been treated and in which the treatment has not been effective in preventing deterioration or reversing the disease process, or both.

[0060] As used herein, "abnormal cell growth" means cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including abnormal proliferation of normal cells and proliferation of abnormal cells.

[0061] A "neoplasm," as used herein, is an abnormal, unregulated, and unregulated growth of cells that is distinguished from normal cells by autonomous growth and somatic mutation. As neoplastic cells grow and divide, they pass on their genetic mutations and growth characteristics to progeny cells. A neoplasm, or tumor, is an accumulation of neoplastic cells. In some embodiments, neoplasms can be benign or malignant.

[0062] "Metastasis," as used herein, refers to the spread of tumor cells via lymphatic or blood vessels. Metastasis also refers to the movement of tumor cells by direct spread through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cells migrate to other parts of the body, resulting in a neoplasm in an area distant from the site of original appearance.

[0063] As discussed herein, "angiogenesis" is prominent in tumor formation and metastasis. Angiogenic factors have been found to be associated with several solid tumors, such as rhabdomyosarcoma, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Tumors cannot grow without a blood supply to provide nutrients and remove cellular waste products. Tumors in which angiogenesis is important include solid tumors, such as renal cell carcinoma and hepatocellular carcinoma, and benign tumors, such as acoustic neuroma and neurofibroma. Angiogenesis is associated with blood-borne tumors, such as leukemia. Angiogenesis is thought to play a role in bone marrow abnormalities that lead to leukemia. Preventing angiogenesis can halt the growth of cancerous tumors and damage to subjects caused by the presence of tumors.

[0064] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., in reference to a mammalian subject, e.g., a human subject.

[0065] The terms "treat," "treating," and "treatment" are meant to include the alleviation or suppression of a disorder, disease, or condition; or one or more symptoms associated with a disorder, disease, or condition; or the alleviation or eradication of the cause(s) of the disorder, disease, or condition itself.

[0066] The term "therapeutically effective amount" refers to the amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician.

[0067] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of compatibility with the other components of a pharmaceutical formulation. It must also be suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson See Ed., CRC Press LLC: Boca Raton, FL, 2004.

[0068] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as a diluent or carrier. A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0069] The term "high" when used to describe the expression of a cell surface marker on a cell refers to a high level of expression of the cell surface marker on the cell relative to control cells. A high level of expression can be about a 10-fold increase, about a 100-fold increase, about a 1000-fold increase, about a 10,000-fold increase, about a 20-fold increase, about a 200-fold increase, about a 2000-fold increase, about a 20,000-fold increase, about a 30-fold increase, about a 300-fold increase, about a 3000-fold increase, about a 30,000-fold increase, about a 40-fold increase, about a 400-fold increase, about a 4000-fold increase, about a 40,000-fold increase, about a 5 ... The increase may be a 0-fold increase, about a 5000-fold increase, about a 50,000-fold increase, about a 60-fold increase, about a 600-fold increase, about a 6000-fold increase, about a 60,000-fold increase, about a 70-fold increase, about a 700-fold increase, about a 7000-fold increase, about a 70,000-fold increase, about an 80-fold increase, about an 800-fold increase, about an 8000-fold increase, about an 80,000-fold increase, about a 90-fold increase, about a 2900-fold increase, about a 9000-fold increase, or about a 90,000-fold increase.

[0070] A "high" level of expression is defined as an increase relative to unstained control cells of about 10-fold to about 100-fold, about 100-fold to about 1000-fold, about 20-fold to about 200-fold, about 200-fold to about 2000-fold, about 30-fold to about 300-fold, about 300-fold to about 3000-fold, about 40-fold to about 400-fold, about 400-fold to about 4000-fold, about 50-fold to about The increase may be a 500-fold increase, about a 500-fold increase to about a 5000-fold increase, about a 60-fold increase to about a 600-fold increase, about a 600-fold increase to about a 6000-fold increase, about a 70-fold increase to about a 700-fold increase, about a 700-fold increase to about a 7000-fold increase, about an 80-fold increase to about an 800-fold increase, about an 800-fold increase to about an 8000-fold increase, about a 90-fold increase to about a 9300-fold increase, or about a 900-fold increase to about a 9000-fold increase.

[0071] High levels of expression were approximately one order of magnitude (10 1 ) increase, about two orders of magnitude (10 2 ) increase, about three orders of magnitude (10 3 ) increase, about four orders of magnitude (10 4 ) increase, about five orders of magnitude (10 5 ) may be an increase.

[0072] Cancer, tumor, tumor-related disorder, and neoplastic disease conditions are serious and often life-threatening.These diseases and disorders are characterized by rapid proliferative cell proliferation, and remain the subject of research efforts aimed at identifying therapeutic agents that are effective in treating them.Such agents extend the survival time of patients, inhibit the rapid proliferative cell proliferation associated with neoplasms, or cause the regression of neoplasms. HDAC inhibitors

[0073] HDAC inhibitors are a new class of therapeutic agents that promote differentiation and apoptosis in hematological and solid malignancies through chromatin remodeling and gene expression regulation. HDAC inhibitors can be broadly classified as pan-HDAC inhibitors or selective HDAC inhibitors. While known HDAC inhibitors exhibit considerable structural diversity, they share common features: a moiety that interacts with the enzyme active site and a side chain located inside the channel leading to the active site. This can be seen with hydroxamates such as SAHA, where the hydroxamate group is thought to interact with the active site. In the case of depsipeptides, intracellular reduction of the disulfide bond is thought to create a free thiol group attached to a 4-carbon alkenyl chain that interacts with the active site. The difference between HDAC inhibitors is that they interact with the rim of the HDAC channel, at the end of the channel opposite the active site. This interaction between HDAC inhibitors and the channel rim is thought to explain, at least in part, some of the observed differences in HDAC selectivity between pan-HDAC inhibitors such as SAHA and selective HDAC inhibitors such as depsipeptide.

[0074] Several HDAC inhibitors have been identified, including benzamides (HDAC inhibitors), short-chain fatty acids (i.e., sodium phenylbutyrate); hydroxamic acids (i.e., suberoylanilide hydroxamic acid and thrichostatin A); cyclic tetrapeptides containing a 2-amino-8-oxo-9,10-epoxy-decanoyl moiety (i.e., trapoxin A), and cyclic peptides without a 2-amino-8-oxo-9,10-epoxy-decanoyl moiety (i.e., FK228). Particularly preferred HDAC inhibitors are HDAC inhibitors. HDAC inhibitors have the chemical name N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylamino-methyl]-benzamide and the chemical structure shown below. [ka] HDAC inhibitors are benzamide HDAC inhibitors that have been clinically tested in multiple solid tumors and hematological cancers. HDAC inhibitors are rapidly absorbed, have half-lives of approximately 100 hours, and importantly, changes in histone acetylation persist for several weeks after HDAC inhibitor administration.

[0075] Entinostat, a class I HDAC inhibitor, has shown promising activity. Novel preclinical studies suggest that HDAC inhibitors have immunomodulatory effects on immune suppressor cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and can partially eradicate immunogenic mouse tumors in combination with immune checkpoint blockade. This activity was found to be mediated by the reduction of MSDCs (Kim et al., PNAS 2014, 111:11774-9). These results may be explained by the selective targeting of HDAC inhibitors to such class 1 HDAC enzymes, which have been shown to play a role in the differentiation and activation of Tregs (Shen et al. PLoS One 2012, 7:e30815; Wang et al. JCI 2015, 125:1111-1123) and MDSCs (Youn et al. Nat. Immunol 2013, 14:211-220).

[0076] The methods and results are also described in Tomita et al., "The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat," ONCOIMMUNOLOGY, Taylor and Francis Online, 2016, the entire contents of which are incorporated herein by reference.

[0077] In summary, data from blood samples obtained from ER+ breast cancer patients treated with HDAC inhibitors in combination with exemestane in ENCORE301 demonstrate HDACi-mediated reduction of immunosuppressive MDSCs and immunocompetent CD14+ HLA-DR1 cells in patients. HI These findings provide the first evidence of an increase in monocytes. These findings may explain, in part, the improved overall survival and provide a strong rationale for designing combination trials of HDAC inhibitors with immune checkpoint blockade.

[0078] The reduction in MDSCs in patients treated with HDAC inhibitors is consistent with a recently published preclinical study (Kim et al. PNAS 2014) demonstrating the ability of HDAC inhibitors to enhance the antitumor activity of immune checkpoint inhibitors through the reduction of MDSCs.

[0079] Recent advances in immunotherapy have demonstrated the anti-cancer effects of immune checkpoint inhibition. Entinostat exhibits immunomodulatory activity, including targeting immunosuppressive cells within the tumor microenvironment, as described in Orillion et al., “Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma,” Clinical Cancer Research, American Association for Cancer Research, 23(2017); pp. 5187-5201, the entire contents of which are incorporated herein by reference in their entirety. Entinostat was found to enhance the anti-cancer effects of PD-1 inhibition in two syngeneic mouse tumor models by reducing tumor growth and prolonging survival. histone deacetylase

[0080] HDACs are a family of at least 18 enzymes grouped into three classes (Class I, II, and III). Class I HDACs include, but are not limited to, HDAC1, 2, 3, and 8. Class I HDACs can be found in the nucleus but are thought to associate with transcriptional repressors. Class II HDACs include, but are not limited to, HDAC4, 5, 6, 7, and 9, and can be found in both the cytoplasm and the nucleus. Class III HDACs are thought to be NAD-dependent proteins and include, but are not limited to, members of the sirtuin family of proteins. Non-limiting examples of sirtuin proteins include SIRT1-7. As used herein, the term "selective HDAC" refers to an HDAC inhibitor that does not interact with all three classes of HDACs. Programmed cell death-1 (PD-1)

[0081] PD-1 is a cell surface receptor that is a member of the CD28 family of T cell regulatory factors belonging to the immunoglobulin superfamily of receptors. The human PD-1 gene is located on chromosome 2q37, and the full-length PD-1 cDNA encodes a protein of 288 amino acid residues that shares 60% identity with mouse PD-1. The gene is expressed by CD4 receptors during thymic development. - CD8 - (double negative) Present on thymocytes and expressed upon activation in mature hematopoietic cells such as T and B cells, NKT cells, and monocytes after prolonged antigen exposure.

[0082] Without wishing to be bound by any theory, binding of the ligand PD-L1 to PD-1 is expected to downregulate effector antitumor T cell activity and facilitate immune evasion. This is supported by the finding that PD-1 / PD-L1 expression is associated with poor prognosis in several tumor types, including gastric, ovarian, lung, and renal cancers. PD-1 has been reported to be predominantly expressed by tumor-infiltrating T lymphocytes in melanoma.

[0083] In vitro studies of PD-1 blockade with PD-1-specific antibodies demonstrated enhanced cytotoxic T cell responses to melanoma-specific antigens, including an increase in the frequency of IFN-γ-secreting antigen-specific cells.

[0084] Without being bound by any theory, it is believed that targeting PD-1 may serve as an effective therapeutic strategy against cancer. The primary approach to clinically targeting PD-1 has been through the development of genetically engineered monoclonal antibodies that inhibit the function of PD-1 or PD-L1.

[0085] PD-L1 has also been shown to bind to B7-1 (CD80), an interaction that also suppresses T cell proliferation and cytokine production, but the exact relative contributions of the PD-L1:PD-1 and PD-L1:B7-1 pathways in cancer remain unclear. PD-1-targeted drugs currently in development inhibit both pathways. However, because the binding sites for PD-1 and B7-1 are adjacent but not overlapping, it is possible that drugs could be developed that specifically target one or the other.

[0086] Cancer cells express high levels of PD-L1 on their surface, which can activate the inhibitory PD-1 receptor on any T cells that infiltrate the tumor microenvironment, effectively switching them off. Indeed, upregulation of PD-L1 expression has been demonstrated in many different cancer types (e.g., melanoma [40%–100%], NSCLC [35%–95%], and multiple myeloma [93%]), and high levels of PD-L1 expression have been shown to be associated with poor clinical outcomes. Furthermore, tumor-infiltrating T cells have been shown to express significantly higher levels of PD-1 than T cells infiltrating normal tissues. It is conceivable that the tumor microenvironment may secrete pro-inflammatory cytokines, such as interferon-gamma (IFNγ), to upregulate PD-1 expression on tumor-infiltrating T cells, ensuring their ability to respond to the high levels of PD-L1 expressed in tumors. Pembrolizumab

[0087] Pembrolizumab is a humanized monoclonal IgG4 anti-PD-1 antibody consisting of a high-affinity murine anti-PD-1-derived variable region grafted onto a human IgG4 immunoglobulin molecule with an engineered Fc region for stabilization. Preclinical antitumor activity has been demonstrated in animal models of multiple tumor types. A first-in-human, phase I dose-escalation study was conducted in patients with advanced, refractory malignancies, administered intravenously at dose levels of 1, 3, and 10 mg / kg initially, followed by 4 weeks and then every 2 weeks. The maximum toxicity observed was grade 2 pruritus, and no drug-related grade 3 or higher adverse events (AEs) were observed. Therefore, the maximum tolerated dose was not reached. The half-life ranged from 13.6 to 21.7 days and was not clearly dose-related. Moderate tumor regressions occurred in four patients. The study was then expanded to include patients receiving pembrolizumab at 10 mg / kg every 2 weeks or 2 or 10 mg / kg every 3 weeks in non-randomized cohorts; a total of 135 patients with melanoma were enrolled. Enrollment included 48 patients who had previously received ipilimumab, but none experienced severe immune-related adverse events (irAEs). Seventy-nine percent of patients experienced some AEs, but only 13% experienced severe (grade 3 or 4) drug-related toxicities, including skin rash or pruritus, fatigue, diarrhea, abdominal pain, and liver dysfunction. The highest frequency (23%) of severe toxicities was observed in patients receiving the highest dose (10 mg / kg every 2 weeks), compared with <10% in less highly dosed cohorts. Possibly autoimmune-related AEs included isolated cases of fibrotic pneumonia, kidney damage, hepatitis, diarrhea, hypothyroidism, hyperthyroidism, and adrenal insufficiency. The overall response rate (ORR) based on immune-related response criteria was 38% (44 of 117), with an additional 8 patients experiencing unconfirmed responses. A total of 77% experienced some degree of tumor regression, including 8 patients with stable disease for 24 weeks. Most responses were documented by the first radiological evaluation at week 12. Median progression-free survival extended to 7 months. Biopsies of responding tumors were CD8 + It showed dense infiltration by T cells. MPDL3280A

[0088] MPDL3280A is a human anti-PD-L1 mAb containing an engineered fragment crystallizable (Fc) domain designed to optimize efficacy and safety by minimizing antibody-dependent cellular cytotoxicity (ADCC). Without wishing to be bound by any particular theory, this structure is understood to allow inhibition of PD-1 / PD-L1 interactions while minimizing ADCC-mediated depletion of activated T cells necessary for an effective anti-tumor immune response.

[0089] MPDL3280A is being evaluated in a Phase I trial in patients with locally advanced or metastatic solid tumors. A total of 175 patients have been recruited to date. The antibody was administered as a single agent at escalating doses of ≤1, 3, 10, 15, and 20 mg / kg for a median duration of 127 days. Results from two expansion cohorts have also been reported: a cohort of 85 patients with squamous or non-squamous NSCLC (53 of whom were evaluable for efficacy) and a cohort of 45 patients with metastatic melanoma (35 of whom were evaluable for efficacy). In both cohorts, MPDL3280A was administered at doses of ≤1, 10, 15, and 25 mg / kg every 3 weeks for up to 1 year. MPDL3280A demonstrated durable responses and was well tolerated; efficacy data are summarized in Table 1. Of the 85 patients in the NSCLC cohort, 55% had been heavily pretreated with at least three prior therapies, 81% were current or former smokers, and 19% were never smokers. The 24-week PFS rate was 44% for squamous cell NSCLC and 46% for non-squamous cell NSCLC. Avelumab

[0090] Avelumab (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. In addition to disrupting immunosuppressive signaling induced by binding of PD-L1 on tumor cells to PD-1 on tumor-infiltrating immune cells, avelumab is designed to mediate antibody-dependent cellular cytotoxicity (ADCC). The ability of avelumab to induce lysis of human cancer cells has been assessed using whole peripheral blood mononuclear cells (PBMCs) or purified natural killer (NK) cells as effectors.

[0091] In a recent study using PBMCs as effectors (Kwong-Yok Tsang et al., Antibody dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody, avelumab (MSB0010718C), on human tumor cells, 2015 ASCO Annual Meeting, J Clin Oncol 33, 2015 (suppl; abstr 3038)), avelumab was found to induce ADCC in 8 of 18 human cancer cell lines. Furthermore, tumour cell lysis was found to positively correlate with the percentage of PD-L1-positive tumour cells, which was reported as mean fluorescence intensity (MFI) determined using flow cytometry. Lysis was increased when NK cells were used as effectors. Pretreatment of tumour cell lines with IFN-γ increased PD-L1 expression but only increased lysis in 4 of 10 cell lines. Preactivation of NK cells with IL-12, however, increased lysis, suggesting a potential synergistic effect of combining avelumab with IL-12-based therapy. Little to no lysis was observed in NK-mediated ADCC assays compared with whole PBMCs or dendritic cells isolated from PBMCs. Tumor cell lines insensitive to lysis by CD8+ T cells were lysed by ADCC using NK cells and avelumab. In conclusion, this study found that avelumab induced lysis of many human tumor cell lines via ADCC. Further clinical trials are needed to determine whether additional mechanisms of ADCC-mediated tumor lysis enhance clinical activity compared with similar agents without ADCC activity. CTLA4-blocking antibodies

[0092] Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is a T-cell surface molecule first identified by differential screening of a mouse cytotoxic T-cell cDNA library. CTLA4 is also a member of the immunoglobulin (Ig) superfamily; CTLA4 contains a single extracellular Ig domain. CTLA4 transcripts have been found in T-cell populations with cytotoxic activity, suggesting that CTLA4 may function in cytolytic responses. Anti-CTLA4 antibodies have demonstrated the ability to enhance the degree of protective immunity in subjects already immunized against protective antigens from pathogens, such as cancer antigens or antigens from infectious agents. Antibodies against CTLA4 have been described for the treatment of cancer. Specifically, there has been growing interest in the therapeutic potential of blocking CTLA4 using antagonist antibodies to CTLA, such as ipilimumab (FDA-approved for melanoma in 2011) and tremelimumab (not FDA-approved), as a means of inhibiting the immune system's tolerance of tumors and thereby providing a potentially effective immunotherapy strategy for patients with cancer. lung cancer

[0093] Lung cancer is the leading cause of cancer deaths among women and men both in the United States and worldwide. It has surpassed breast cancer as the leading cause of cancer deaths among women. Lung cancer is expected to cause 158,040 deaths in the United States in 2014, more than the number of deaths from colon and rectal, breast, and prostate cancer combined. While lung cancer diagnosed at its earliest stages has a high survival rate, with approximately 49% surviving five years or longer, only about 2% of people diagnosed with lung cancer that has spread to other parts of the body survive five years after diagnosis.

[0094] Cancer occurs when normal cells undergo a transformation that causes them to grow and proliferate without control. The cells form a mass, or tumor, that is distinct from the surrounding tissue in which they originate. Tumors are dangerous because they deprive healthy cells of oxygen, nutrients, and space, and because they invade, disrupting or reducing the ability of normal tissue to function.

[0095] Most lung tumors are malignant, meaning they can invade and destroy surrounding healthy tissue and spread throughout the body. Tumors can spread to nearby lymph nodes or through the bloodstream to other organs. This process is called metastasis. When lung cancer metastasizes, the tumor in the lung is called the primary tumor, and tumors in other parts of the body are called secondary or metastatic tumors.

[0096] Some tumors in the lungs are metastases from cancers elsewhere in the body. The lungs are a common site of metastasis. In this case, the cancer is not considered lung cancer. For example, if prostate cancer spreads to the lungs through the bloodstream, it is metastatic prostate cancer in the lungs (a secondary cancer) and is not called lung cancer.

[0097] Lung cancer comprises a group of different tumor types. It is usually divided into two major groups, accounting for approximately 95% of all cases. The division into groups is based on the type of cells that make up the cancer. The two major types of lung cancer are characterized by the size of the tumor cells when viewed under a microscope. They are called small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC includes several tumor subtypes. SCLC is less common but grows more rapidly and is more likely to metastasize than NSCLC. In many cases, SCLC has already spread to other parts of the body by the time the cancer is diagnosed. Approximately 5% of lung cancers have rare cell types, including carcinoid tumors and lymphomas. As used herein, the term "lung cancer" includes, but is not limited to, SCLC, NSCLC, carcinoid tumors, lymphomas, and their various subtypes. non-small cell lung cancer

[0098] NSCLC is a type of lung cancer that does not fall under the small cell carcinoma (oat cell carcinoma) category. The term "non-small cell lung cancer" refers to various types of bronchogenic carcinoma (cancer that originates in the lining of the bronchi). Examples of specific types of NSCLC include, but are not limited to, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (i.e., large cell undifferentiated carcinoma).

[0099] Adenocarcinoma is cancer that develops in the lining, or inner surface, of an organ. It is the most common type of lung cancer, accounting for 30% to 40% of all cases. A subtype of adenocarcinoma is called bronchoalveolar cell carcinoma, which has a pneumonia-like appearance on chest x-rays.

[0100] Squamous cell carcinoma is cancer that begins in squamous epithelial cells. Squamous cells are thin, flat cells that look like fish scales under a microscope. They are found on the surface of the skin, lining the body's hollow organs, and in tissues that form the passageways of the respiratory and digestive tracts. Squamous cell carcinoma can arise in any of these tissues. Squamous cell carcinoma is the second most common type of lung cancer, accounting for approximately 30% of all cases.

[0101] Large cell carcinomas show no evidence of squamous or glandular maturation. Therefore, these tumors are often diagnosed by default when all other possibilities have been ruled out. These tumors lack any diagnostic features that would suggest their diagnosis before biopsy. They tend to grow rapidly, metastasize early, and are strongly associated with smoking. Large cell tumors are usually large, bulky, well-circumscribed, grayish-pink masses with extensive hemorrhage and necrosis. They generally have central necrosis, but rarely cavitation. They tend to be located in the central to peripheral lung regions. They may also spread locally, including to segmental or subsegmental bronchi. A variant of large cell carcinoma is giant cell carcinoma. This subtype is particularly aggressive and has a very poor prognosis. These tumors typically present as large peripheral masses with focal necrotic components. These tumors do not involve the large airways unless they directly extend. Large cell carcinoma accounts for 10% to 20% of all cases of lung cancer. melanoma

[0102] Melanoma is a malignant tumor of melanocytes, the cells that produce the pigment melanin, derived from the neural crest. Most melanomas arise in the skin, but they can also arise on mucosal surfaces or in other sites to which neural crest cells migrate, including the uvea. Uveal melanoma differs significantly from cutaneous melanoma in incidence, prognostic factors, molecular characteristics, and treatment.

[0103] In 2014, 9,710 deaths from melanoma were predicted in the United States, with an estimated 76,100 new cases. Skin cancer is the most common malignancy diagnosed in the United States, with 3.5 million cancers diagnosed in 2 million people each year. Melanoma accounts for less than 5% of skin cancers but causes the most deaths. Incidence has been increasing over the past 40 years. Older men are at highest risk; however, melanoma is the most common cancer in young adults aged 25-29 and the second most common cancer in those aged 15-29. Ocular melanoma is the most common eye cancer, with approximately 2,000 cases diagnosed each year.

[0104] Melanoma occurs primarily in adults, with over 50% of cases arising in apparently normal areas of the skin. Melanoma can occur anywhere, including mucosal surfaces and the uvea, but in women, melanoma occurs more commonly on the extremities, and in men, it occurs most commonly on the trunk or head and neck.

[0105] Prognosis is influenced by primary and metastatic tumor characteristics. The most important prognostic factors include, but are not limited to, melanoma thickness or level of invasion, mitotic index defined as mitoses per millimeter, ulceration or bleeding at the primary site, number of involved regional lymph nodes with characteristics of macro- and micrometastases, systemic metastasis, location—nonvisceral versus pulmonary versus all other visceral sites, and elevated serum lactate dehydrogenase levels. Without being bound by any theory, it is believed that the presence of tumor-infiltrating lymphocytes may be a potential prognostic factor. breast cancer

[0106] Breast cancer is cancer that develops in breast tissue. Signs of breast cancer can include a lump within the breast, changes in breast shape, dimpling of the skin, nipple leakage, or scaly red patches on the skin. Patients with metastatic disease may experience bone pain, lymphadenopathy, difficulty breathing, or jaundice. Breast cancer outcomes vary depending on the type of cancer, the extent of the disease, and the patient's age. Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases. In 2012, there were 168 million cases and 522,000 deaths. It is more common in developed countries and is over 100 times more common in women than in men. Breast cancer is classified using several grading systems. Each of these systems can affect prognosis and may also influence treatment. Breast cancer is usually classified primarily by its histological appearance. Most breast cancers originate from the epithelium lining the ducts or lobules, and these cancers are classified as ductal or lobular carcinoma. Non-invasive carcinoma is the growth of low-grade cancerous or pre-cancerous cells within a specific tissue compartment, such as the breast duct, without invading surrounding tissue. In contrast, invasive carcinoma does not confine itself to the original tissue compartment.

[0107] Breast cancer staging using the TNM system is based on tumor (T) size, whether the tumor has spread to nearby lymph nodes (N), and whether the tumor has metastasized (M) to more distant parts of the body. Larger size, nodal involvement, and metastasis have higher stage numbers and poorer prognoses. The major stages are stage 0, stages 1-3, and stage 4. Stage 0 is a precancerous or marker condition, namely, ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). Stages 1-3 are confined to the breast or regional lymph nodes. Stage 4 is metastatic cancer with a less favorable prognosis.

[0108] Breast cancer cells have receptors on their surface and in their cytoplasm and nucleus. Chemical messengers, such as hormones, bind to the receptors, which cause changes in the cells. Breast cancer cells may or may not have three important receptors: estrogen receptor (ER), progesterone receptor (PR), and HER2. Therefore, breast cancer is divided into hormone receptor-positive or ER- / PR-positive breast cancer, HER2-positive breast cancer, and triple-negative breast cancer, which is negative for ER, PR, and HER2.

[0109] Myeloid-derived suppressor cells have been shown to have several important clinical correlates in breast cancer. In preclinical models of breast cancer, myeloid-derived suppressor cell levels correlate positively with tumor size and inversely with T cell proliferation. In clinical settings, baseline levels of circulating myeloid-derived suppressor cells correlate with disease burden, metastatic spread, and reduced survival in metastatic breast cancer. Baseline levels of circulating myeloid-derived suppressor cells have also been shown to correlate with response to adjuvant chemotherapy in HER2-negative breast cancer, with increased levels indicating a poorer response to chemotherapy. Hormone receptor-positive breast cancer

[0110] Hormones such as estrogen and progesterone promote the growth of hormone receptor-positive cancers. Approximately two out of three breast cancers are hormone receptor-positive because they contain receptors for the hormones estrogen (ER-positive breast cancer) or progesterone (PR-positive breast cancer). Because these breast cancers depend on hormones for growth, therapies have been designed to reduce the estrogen levels or stop estrogen activity in breast cancer cells.

[0111] Non-limiting examples of therapies that block estrogen activity include tamoxifen, toremifene, and fulvestrant. Tamoxifen blocks estrogen from binding to estrogen receptors in breast cancer cells. Tamoxifen acts like an anti-estrogen in breast cells but functions like an estrogen in other tissues, such as the uterus and bone. Because tamoxifen acts like an estrogen in some tissues but like an anti-estrogen in others, it is called a selective estrogen receptor modulator (SERM). Toremifene is another SERM approved for the treatment of metastatic breast cancer. Fulvestrant is a drug that first blocks estrogen receptors, triggering their degradation. Fulvestrant is not a SERM because it acts like an anti-estrogen throughout the body. Fulvestrant is used to treat metastatic breast cancer after other hormone therapies, such as tamoxifen, have stopped working.

[0112] Aromatase inhibitors (AIs) function to block estrogen production in postmenopausal women. Aromatase inhibitors work by blocking aromatase, which converts androgens produced in adipose tissue and the brain. Non-limiting examples of aromatase inhibitors include letrozole, anastrozole, and exemestane. triple negative breast cancer

[0113] Triple-negative breast cancer, characterized by tumors that do not express the estrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, presents a significant clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. While the metastatic potential of triple-negative breast cancer is similar to that of other breast cancer subtypes, these tumors are associated with shorter median time to recurrence and death. Therefore, one important goal is to identify prognostic factors and markers to reliably select high- and low-risk subsets of patients with triple-negative disease for different treatment approaches for subtypes with differential responsiveness to specific agents. However, reliable prognostic markers are elusive, and the utility of markers is inconsistent. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still no consensus on a standard assay or EGFR expression level cutoff for prognosis. Similarly, because triple-negative status is sometimes used as a surrogate for basal-like breast cancer, specific basal-like test markers are being investigated. Indeed, trials designed to recruit patients with basal-like breast cancer using ER / PR and HER-2 negativity can only provide an approximation of the triple-negative population, and although they are sometimes reanalyzed using more specific indicators such as CK5 / 6, EGFR status, etc., they still suffer from discordance.

[0114] Chemotherapy remains the mainstay of triple-negative breast cancer treatment, but even with significant clinical advances, significant limitations still need to be overcome within the next few years. Current treatment strategies for triple-negative disease include anthracyclines, taxanes, ixabepilone, platinum-based agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple-negative breast cancer, although results have been inconsistent. Agents targeting poly(ADP-ribose) polymerase and the androgen receptor have also been proposed for these patients or subsets, and ongoing trials are expected to provide definitive guidance regarding the value of these agents in triple-negative disease. Triple-negative breast cancer is clearly a distinct clinical subtype in terms of both ER and HER-2 expression, but further subclassification is needed. Currently, there is no clear, proven, and effective single agent that targets the critical weakness of triple-negative breast cancer.

[0115] Various subtypes of triple-negative breast cancer include basal-like TNBC (basal-like 1 and 2 (BL-1, BL-2), immunomodulatory (IM)) and mesenchymal stem cell-like triple-negative breast cancer (MSL), and luminal androgen receptor (LAR) subtypes.

[0116] PD-L1 is expressed in many cancers, including renal cell carcinoma, pancreatic cancer, ovarian cancer, gastric cancer, esophageal cancer, and hepatocellular carcinoma. Studies have confirmed PD-L1 expression in 50% (22 of 44 tumor types evaluated in breast cancer studies). In 15 (34%), expression was limited to the tumor epithelium, whereas in 18 (41%), it was detected in tumor-infiltrating lymphocytes. Furthermore, intratumoral PD-L1 expression was found to be associated with high histological grade and negative hormone receptor status. Consistent with previous studies, another study found that approximately 20% of TNBC tumors expressed PD-L1. The majority (95%) of these TNBC tumors were grade 3.

[0117] Without wishing to be bound by any particular theory, we hypothesize that a possible mechanism by which tumors can drive PD-L1 expression is through oncogenic signaling pathways. This was first demonstrated in glioblastoma, where PTEN loss was observed to be associated with increased PD-L1 expression, suggesting the involvement of the PI3K pathway. Because PTEN loss is commonly observed in TNBC, we investigated the relationship between PTEN and PD-L1 expression in this study. Loss of PTEN staining was observed in approximately 50% of TNBC tumors included in a breast cancer tissue microarray with PD-L1 expression >5%. Similarly, in a panel of TNBC cell lines, two exemplary cell lines showing PTEN loss, MDA-MB-468 and BT-549, were found to have high cell surface PD-L1 expression. Collectively, these data suggest that multiple mechanisms of PD-L1 regulation may exist in TNBC. ovarian cancer

[0118] Ovarian cancer is the eighth most common cancer in women worldwide, with an estimated 225,500 new cases diagnosed each year and an estimated 140,200 deaths each year.

[0119] There are three basic types of ovarian tumors: epithelial, germ cell, and stromal cell. Epithelial tumors begin in the cells that cover the outer surface of the ovaries, and most ovarian tumors are epithelial cell tumors. Germ cell tumors begin in the cells that produce eggs. Stromal tumors begin in the cells that hold the ovaries together and produce female hormones. Significant risk factors for ovarian cancer include a deficiency in DNA repair via homologous recombination, such as mutations in the BRCA1 or BRCA2 genes. These genes, originally identified in families with multiple cases of breast cancer, are associated with approximately 5 to 10 percent of ovarian cancers.

[0120] Potential treatments for ovarian cancer include surgery, immunotherapy, chemotherapy, hormone therapy, radiation therapy, or a combination thereof. Surgical procedures for the treatment of ovarian cancer include debulking and unilateral or bilateral oophorectomy and / or unilateral or bilateral salpingectomy. Anticancer drugs also used to treat ovarian cancer include cyclophosphamide, etoposide, altretamine, and ifosfamide. Hormone therapy with the drug tamoxifen has also been used to shrink ovarian tumors. Radiation therapy optionally includes external beam radiation therapy and / or brachytherapy. The majority of newly diagnosed ovarian cancer patients have been shown to respond to first-line platinum-based and paclitaxel chemotherapy. However, 50-80% of patients who respond to this combination therapy eventually relapse. See, e.g., Herzog, "Update on the role of topotecan in the treatment of recurrent ovarian cancer," The Oncologist 7(Suppl. 5):3-10 (2002). Women with advanced ovarian cancer have poor long-term survival due to disease recurrence, with most dying within five years. Ovarian cancer that recurs within six months of platinum treatment is generally a heterogeneous spectrum disease with a low response rate (approximately 10%-25%) to short-term therapy. Attempts to identify patients who will respond to specific drugs are difficult. Current treatment options for recurrent ovarian cancer clearly need improvement.

[0121] The terms "heavily pretreated recurrent ovarian cancer" and "platinum-resistant ovarian cancer," as used herein, refer to ovarian cancer that has been treated with one or more rounds of platinum-based chemotherapy using agents such as cisplatin, gemcitabine, carboplatin, and the like.

[0122] PD-L1 is expressed in many cancers, including renal cell carcinoma, pancreatic cancer, ovarian cancer, gastric cancer, esophageal cancer, and hepatocellular carcinoma. It has been shown that PD-L1 expression on monocytes in the ascites and blood of patients with malignant ovarian cancer is significantly higher than that of patients with benign / borderline disease, with no overlap between these groups. Furthermore, recent studies have shown that most ovarian cancers evade the host immune system and accelerate tumor growth by expressing PD-L1. Therefore, it is hypothesized that the PD-1 / PD-L pathway may be a promising target for immunotherapy of ovarian cancer. Methods for selecting patients for combination therapy

[0123] In certain embodiments, the methods of the present disclosure include measuring CD14-positive, HLA-DR-high and / or CD16-negative cells and measuring peripheral blood mononuclear cells to determine the administration of combination therapy to a patient diagnosed with cancer.

[0124] In some embodiments, the method further comprises selecting a patient for combination therapy if the percentage of CD14-positive, HLA-DR-high and / or CD16-negative cells in total peripheral blood mononuclear cells is greater than about 20%.

[0125] In some embodiments, the method further comprises selecting a patient who is worsening from a prior treatment.

[0126] In some embodiments, the method further comprises selecting a combination therapy comprising entinostat and a second therapeutic agent.

[0127] Non-limiting examples of second therapeutic agents include anti-PD-1 antibodies, such as nivolumab and pembrolizumab; anti-PD-L1 antibodies, such as MPDL3280A; and CTLA4 blocking antibodies, such as ipilimumab and tremelimumab. Non-limiting examples of cancers include lung cancer, such as non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (i.e., large cell undifferentiated carcinoma). In some embodiments, the second therapeutic agent is pembrolizumab, and the cancer is lung cancer. In some embodiments, the second therapeutic agent is pembrolizumab, and the breast cancer is non-small cell lung cancer. In some embodiments, the second therapeutic agent is pembrolizumab, and the cancer is melanoma.

[0128] In some embodiments, entinostat is administered orally. In some embodiments, entinostat is administered orally and the anti-PD-1 antibody, anti-PD-L1 antibody, or CTLA4 blocking antibody is administered by infusion. Non-limiting examples of infusion include subcutaneous infusion, intravenous infusion, intraperitoneal infusion, and infusion via osmotic pump.

[0129] In some embodiments, entinostat is administered first in the combination therapy. In some embodiments, entinostat is administered weekly. In some embodiments, entinostat is administered every two weeks.

[0130] The entinostat, exemestane, anti-PD-1 antibody, anti-PD-L1 antibody, or CTLA4 blocking antibody can be administered about every day, about every 2 days, about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every week, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every month, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, or about every 2 months. Entinostat, anti-PD-1 antibody, anti-PD-L1, or CTLA4 blocking antibody can be administered about every day to about every 2 days, about every 2 days to about every 3 days, about every 3 days to about every 4 days, about every 4 days to about every 5 days, about every 5 days to about every 6 days, about every 6 days to about every week, about every week to about every 2 weeks, about every 2 weeks to about every 3 weeks, about every 3 weeks to about every 4 weeks, about every 4 weeks to about every month, about every month to about every 5 weeks, about every 5 weeks to about every 6 weeks, about every 6 weeks to about every 7 weeks, about every 7 weeks to about every 8 weeks, or about every 8 weeks to about every 2 months.

[0131] In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative, and peripheral blood mononuclear cells are circulating and are measured in peripheral blood by obtaining a peripheral blood sample. In some embodiments, the peripheral blood sample is treated with an anticoagulant. In some embodiments, the peripheral blood sample is collected or transferred into an anticoagulant-containing container. Non-limiting examples of anticoagulants include heparin, heparin sodium, potassium oxalate, EDTA, and sodium citrate. In some embodiments, the peripheral blood sample is treated with an erythrocyte lysing agent. In some embodiments, peripheral blood mononuclear cells are measured in a tissue biopsy.

[0132] In some embodiments, the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells and peripheral blood mononuclear cells are measured in a peripheral blood sample, and the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells among total peripheral blood mononuclear cells is determined.

[0133] In some embodiments, the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total peripheral blood mononuclear cells is used to select patients for administration of a combination therapy comprising an HDAC inhibitor and a second therapeutic agent. CD14 positive

[0134] In some embodiments, the percentage of CD14 positive cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0135] In some embodiments, the percentage of CD14 positive cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, and about 45% to about 50%. High HLA-DR

[0136] In some embodiments, the percentage of HLA-DR-high cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25% , at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0137] In some embodiments, the percentage of HLA-DR-high cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 20% to about 30% about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, and about 45% to about 50%. CD16 negative

[0138] In some embodiments, the percentage of CD16 negative cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0139] In some embodiments, the percentage of CD16-negative cells relative to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, and about 45% to about 50%. CD14 positive and HLA-DR high

[0140] In some embodiments, the percentage of CD14 positive and HLA-DR-high cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0141] In some embodiments, the percentage of CD14 positive and HLA-DR high cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, About 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, and about 45% to about 50%. CD14 positive and CD16 negative

[0142] In some embodiments, the percentage of CD14 positive and CD16 negative cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0143] In some embodiments, the percentage of CD14-positive and CD16-negative cells relative to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50 ... 0% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, and about 45% to about 50%. High HLA-DR and negative CD16

[0144] In some embodiments, the percentage of HLA-DR-high and CD16-negative cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 7 at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0145] In some embodiments, the percentage of HLA-DR-high and CD16-negative cells relative to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, About 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, and about 45% to about 50%. CD14 positive, HLA-DR high and CD16 negative

[0146] In some embodiments, the percentage of CD14 positive, HLA-DR-high and CD16 negative cells to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0147] In some embodiments, the percentage of CD14 positive, HLA-DR high, and CD16 negative cells relative to total peripheral blood mononuclear cells in a peripheral blood sample or tissue biopsy is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15 ...5%, about 15% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15 0%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, and about 45% to about 50%.

[0148] In some embodiments, the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells per unit volume of a biological sample is determined. Non-limiting examples of unit volume include picoliters (pL), nanoliters (nL), microliters (μL), milliliters (mL), deciliters (dL), and liters (L). In some embodiments, the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells per unit volume of a biological sample is used to select patients for administration of a combination therapy comprising an HDAC inhibitor and a second therapeutic agent. In some embodiments, the biological sample is a peripheral blood sample.

[0149] In some embodiments, the number of CD14 positive, HLA-DR high, and / or CD16 negative cells per unit volume of a biological sample is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 60 0, about 700, about 800, about 900, about 1000, about 1500, about 2000, about 2500, about 3000, about 3500, about 4000, about 4500, about 5000, about 6000, about 7000, about 8000, about 9000, about 10000, about 15000, about 20000, about 25000, about 30000, about 35000, about 40000, about 45000, about 50000, about 60000, about 70000, about 80000, about 90000 or about 100000.

[0150] In some embodiments, the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells per unit volume of a biological sample is about 1 to about 2, about 2 to about 3, about 3 to about 4, about 4 to about 5, about 5 to about 6, about 6 to about 7, about 7 to about 8, about 8 to about 9, about 9 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 45 pieces, 45 pieces to 50 pieces, 50 pieces to 60 pieces, 60 pieces to 70 pieces, 70 pieces to 80 pieces, 80 to 90 pieces, 90 to 100 pieces, 100 to 150 pieces, 150 to 200 pieces, 200 to 250 pieces , about 250 to about 300 pieces, about 300 to about 350 pieces, about 350 to about 400 pieces, about 400 to about 450 pieces, about 450 to about 500 pieces, about 500 to about 600 pieces, about 600 to about 700 pieces, about 700 to about 800 pieces, about 800 to about 900 pieces, about 900 pieces to about 1000 pieces, about 1000 pieces to about 1500 pieces, about 1500 pieces to about 2000 pieces, about 2000 pieces to about 2500 pieces, about 2500 pieces to about 3000 pieces, about 3000 pieces to about 3500 pieces, about 3500 pieces to about 4000 pieces, about 4000 pieces to about 4500 pieces, about 4500 pieces to about 5000 pieces, about 5000 pieces to about 6000 pieces, about 6000 pieces to about 7000 pieces, about 7000 pieces to about 8000 pieces, about 8000 pieces to about 9000 pieces, about 9000 pieces to about 10000 pieces, about 10000 pieces to about 15,000, about 15,000 to about 20,000, about 20,000 to about 25,000, about 25,000 to about 30,000, about 30,000 to about 35,000, about 35,000 to about 40,000, about 40,000 to about 45,000, about 45,000 to about 50,000, about 50,000 to about 60,000, about 60,000 to about 70,000, about 70,000 to about 80,000, about 80,000 to about 90,000, or about 90,000 to about 100,000.

[0151] In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells and peripheral blood mononuclear cells are measured using flow cytometry, mass cytometry, cytospin, or immunohistochemistry.

[0152] Flow cytometry is a laser-based technique used in cell counting, cell sorting, and biomarker detection by suspending cells in a liquid stream and passing them through an electronic detection device. Flow cytometry allows simultaneous multiparametric analysis of the physical and chemical characteristics of up to thousands of particles per second.

[0153] Mass cytometry is a mass spectrometry technique based on inductively coupled plasma mass spectrometry for determining cellular identity and function. In this technique, binding agents are tagged with isotopically pure rare earth elements. These binding agents are then applied to tag cells and their components. The cells are nebulized and sent through an argon plasma laser, which ionizes the polyatomic rare earth element tags. The ionized tagged cells are then analyzed by a time-of-flight mass spectrometer. Advantages of mass cytometry include its ability to overcome the limitations of flow cytometry due to spectral overlap.

[0154] Cytospinning is a technique in which suspended cells are centrifuged onto a glass slide as a smear for cell staining and cell counting. Concentrated cell suspensions in low-viscosity media are good candidates for smear preparation. Dilute cell suspensions in thin media are best prepared for cytospin via cytocentrifugation. Cell suspensions in high-viscosity media are best suited for testing as swab preparations. A common feature of these preparations is that the entire cells are present on the slide surface.

[0155] Immunohistochemistry is a type of histological staining for detecting intracellular antigens in tissue sections by utilizing the principle of antibodies specifically binding to antigens in biological tissues. Visualization of antibody-antigen interactions can be achieved in several ways. Antibodies can be conjugated to enzymes, such as peroxidase, that can catalyze a color-producing reaction. Alternatively, antibodies can be tagged with fluorescent substances, such as fluorescein or rhodamine.

[0156] In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells and peripheral blood mononuclear cells are identified by cell surface markers. Non-limiting examples of cell surface markers that identify peripheral blood mononuclear cells include CD3, CD14, CD19, CD56, and HLA-DR.

[0157] In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells are identified by the absence of CD14, high levels of HLA-DR, and CD16, and peripheral blood mononuclear cells are identified by CD3. In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells are identified by the absence of CD14, high levels of HLA-DR, and CD16, and peripheral blood mononuclear cells are identified by CD14. In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells are identified by the absence of CD14, high levels of HLA-DR, and CD16, and peripheral blood mononuclear cells are identified by CD19. In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells are identified by the absence of CD14, high levels of HLA-DR, and CD16, and peripheral blood mononuclear cells are identified by CD56. In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells are identified by the absence of CD14, high levels of HLA-DR, and CD16, and peripheral blood mononuclear cells are identified by HLA-DR. In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells are identified by the absence of CD14, high levels of HLA-DR, and CD16, and peripheral blood mononuclear cells are identified by CD3, CD14, CD19, CD56, and HLA-DR. In some embodiments, CD14-positive, HLA-DR-high, and / or CD16-negative cells are identified by the absence of CD14, high levels of HLA-DR, and CD16, and peripheral blood mononuclear cells are identified by CD14. Additional therapy

[0158] Available additional treatments for the cancers described herein that may be advantageously employed in combination with the therapies disclosed herein include, but are not limited to, adjuvant radiation therapy, chemotherapy, antibody therapy, and tyrosine kinase inhibitors.

[0159] Radiation therapy is a cancer treatment that uses high-energy X-rays or other types of radiation to kill cancer cells or prevent them from growing. Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells by killing cells or stopping them from dividing. When chemotherapy is taken orally or injected into blood vessels or muscles, the drugs can enter the bloodstream and reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is administered directly to the spine, organs, or body cavities, such as the abdomen, the drugs mainly affect cancer cells in these areas (regional chemotherapy). The method of administering chemotherapy depends on the type and stage of the cancer being treated.

[0160] Different chemotherapeutic agents are known in the art for treating lung cancer. Cytotoxic agents used to treat lung cancer include carboplatin (e.g., Paraplatin®, Paraplat®), cisplatin (e.g., Platinol®, Platinol-Aq®), crizotinib (e.g., Xalkori®), etoposide (e.g., Toposar®, VePesid®), etoposide phosphate (e.g., Etopophos®), gemcitabine hydrochloride (e.g., Gemzar®), gemcitabine-cisplatin, methotrexate (e.g., Abitrexate®, Folex®, Folex Pfs®, Methotrexate®). Lpf®, Mexate®, Mexate-Aq®), paclitaxel (e.g., Taxol®), pemetrexed disodium (e.g., Alimta®), topotecan hydrochloride (e.g., Hycamtin®), and erlotinib (e.g., Tarceva®).

[0161] A variety of agents are known in the art for treating melanoma, including aldesleukin (e.g., Proleukin®), dabrafenib (e.g., Tafinlar®), dacarbazine (e.g., DTIC-Dome®), recombinant interferon alpha-2b (e.g., Intron® A), ipilimumab (e.g., Yervoy®), pembrolizumab (e.g., Keytruda®), trametinib (e.g., Mekinist®), nivolumab (e.g., Opdivo®), pegylated interferon alpha-2b (e.g., Pegintron®, Sylatron®), vemurafenib (e.g., Zelboraf®).

[0162] A variety of agents are known in the art for treating breast cancer, including aromatase inhibitors such as anastrazole (such as Arimidex®), exemestane (e.g., Aromasin®), fadrozole (such as Afema®), formestane (such as Lentaron®), letrozole (such as Femara®), and vorozole (such as Rivizor®).

[0163] Monoclonal antibody therapy is a cancer treatment that uses antibodies created in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells that may help them grow or normal substances. The antibodies bind to the substances, kill the cancer cells, block cancer cell growth, or prevent cancer cells from spreading. Monoclonal antibodies are given by infusion. Monoclonal antibodies can be used alone or to deliver drugs, toxins, or radioactive materials directly to cancer cells. Monoclonal antibodies are also used in combination with chemotherapy as adjuvant therapy.

[0164] Further illustrative treatments that may be advantageously combined with the compositions and therapies disclosed herein include, but are not limited to, administration of agents including, but not limited to, lapatinib alone or in combination with capecitabine, docetaxel, epirubicin, epothilone A, B, or D, goserelin acetate, paclitaxel, pamidronate, bevacizumab, or trastuzumab.

[0165] In some embodiments, the additional therapy comprises chemotherapy comprising administering to the subject one or more of doxorubicin, cyclophosphamide, paclitaxel, lapatinib, capecitabine, trastuzumab, bevacizumab, gemcitabine, eribulin, or nab-paclitaxel. Oral formulation

[0166] Oral formulations containing the pharmaceutically active ingredients described herein can include any conventionally used oral form, including tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, liquids, wafers, sprinkles, elixirs, syrups, buccal forms, and oral liquids. Capsules may contain a mixture of the active compound(s) with an inert filler or diluent, such as pharmaceutically acceptable starch (e.g., corn, potato, or tapioca starch), sugar, artificial sweeteners, powdered cellulose, such as crystalline and microcrystalline cellulose, flour, gelatin, gum, etc. Useful tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods, utilizing pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents, or stabilizers, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch, and powdered sugar. In some embodiments, surface modifiers include nonionic and anionic surface modifiers. For example, surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize standard delay- or time-release formulations to alter the absorption of the active compound(s).The oral formulation may also consist of administering the active ingredient in water or fruit juice, containing suitable solubilizers or emulsifiers as needed. Oral administration

[0167] As described herein, the combination therapy described herein can be administered simultaneously or in a staggered regimen, in which the HDAC inhibitor or entinostat is administered at a different time during the course of chemotherapy compared to the second pharmaceutical agent. This time difference can range from minutes, hours, days, weeks, or longer between the administration of the two components. Thus, the term combination does not necessarily mean administration at the same time or as a single dose, but each component is administered within the desired treatment period. The agents can also be administered by different routes. As is common with chemotherapy regimens, the course of chemotherapy can be repeated after several weeks, and the administration of the two compounds can follow the same time frame, with modifications based on the patient's response.

[0168] In other embodiments, the pharmaceutical compositions provided herein may be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, liquids, emulsions, suspensions, solutions, wafers, dusting powders, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, and flavoring agents.

[0169] Binders or granulating agents impart cohesive properties to the tablet and ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of caraway, panwar gum, ghatti gum, isagol husk mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein in an amount of from about 50% to about 99% by weight.

[0170] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amount, can give some compressed tablets the property of being able to disintegrate in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0171] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pith; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; align; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5% to about 15% by weight, or about 1% to about 5% by weight of disintegrant.

[0172] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as glyceryl behenate and polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil, zinc stearate, ethyl oleate, ethyl laurate, agar, starch, lycopodium, silica or silica gel, such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA), and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1% to about 5% by weight of a lubricant.

[0173] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Coloring agents include any approved, certified water-soluble FD&C dyes, and water-insoluble FD&C dyes suspended on alumina hydrate, and lake colors, and mixtures thereof. Lake colors are combinations of water-soluble dyes adsorbed to hydrous oxides of heavy metals, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0174] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[0175] In further embodiments, the pharmaceutical compositions provided herein may be provided as compressed tablets, molded tablets, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammonia-containing shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle and include layered tablets and press-coated or dry-coated tablets.

[0176] Tablet dosage forms can be prepared with the active ingredient in powdered, crystalline, or granular form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, or colorants. Flavorings and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0177] The pharmaceutical compositions provided herein may be provided as soft or hard capsules made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two sections that slide over one another, completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methyl and propyl parabens and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules may be coated as known to those skilled in the art to modify or maintain dissolution of the active ingredient.

[0178] In other embodiments, the pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of small globules, and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are sweetened, clear, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, for example, water, to be conveniently measured for administration.

[0179] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 represent the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0180] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle-type dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0181] In other embodiments, the pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders that can be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and carbon dioxide sources.

[0182] Coloring and flavoring agents can be used in any of the above dosage forms.

[0183] The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0184] In further embodiments, the pharmaceutical compositions provided herein may be formulated with other active ingredients that do not impair the desired therapeutic effect, or substances that complement the desired effect. In some embodiments, an anti-PD-1 antibody, anti-PD-L1, and / or CTLA4-blocking therapeutic agent, and an HDAC inhibitor are administered within a short period of time (e.g., an anti-PD-1 antibody, anti-PD-L1 and / or CTLA4-blocking therapeutic agent, and an HDAC inhibitor are administered simultaneously). Thus, the present disclosure provides methods for treating or preventing cancer, comprising administering an anti-PD-1 antibody, anti-PD-L1 and / or CTLA4-blocking therapeutic agent, and an HDAC inhibitor within a short period of time. In some embodiments, "within a short period of time" means that the administration of one therapeutic agent occurs within a period of time before or after the administration of another therapeutic agent, such that the therapeutic effects of one therapeutic agent overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, the therapeutic effects of one therapeutic agent completely overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, "within a short period of time" means that the administration of one therapeutic agent occurs within a period of time before or after the administration of another therapeutic agent, such that there is a synergistic effect between the two therapeutic agents. "Within a short period of time" can vary according to various factors, including, but not limited to, the age, sex, weight, genetic background, medical status, medical history, and treatment history of the subject to whom the therapeutic agent is administered; the disease or condition to be treated or ameliorated; the therapeutic result to be achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route(s) by which the therapeutic agent is administered. In some embodiments, "within a short period of time" means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, repeated administration of one therapeutic agent may occur within a short period of time relative to the administration of another therapeutic agent alone. In some embodiments, the term "short period of time" may vary between treatment cycles or dosing regimens. [Example]

[0185] Example 1. Selection of NSCLC patients for entinostat combination therapy with pembrolizumab To select patients for combination treatment with an HDAC inhibitor in combination with a second therapeutic agent, peripheral blood samples were collected from patients. Patients were diagnosed with non-small cell lung cancer that progressed during or failed to respond to anti-PD-1 or anti-PD-L1 treatment. A 5 milliliter (mL) peripheral blood sample was collected in an EDTA blood collection tube, which was rapidly chilled on ice. The blood sample was transferred to a conical tube and diluted with 15 mL of red blood cell lysis buffer and incubated at room temperature for 10 minutes. The red blood cell lysate was quenched by diluting with 30 mL of phosphate-buffered saline (PBS). The cell suspension was centrifuged at 400 × g for 5 minutes at 4°C, and the supernatant was discarded. The pellet was resuspended in 5 mL of PBS and transferred to a new conical tube. The resuspended sample was sedimented with 5 mL of Ficoll®. The cells are centrifuged at 400 x g for 20 minutes with the centrifuge brake off. The nucleated cells are collected at the interface between the PBS and Ficoll® layers and placed in a new conical tube.

[0186] The cells are washed by adding a volume equal to the original blood draw to the pellet in a new conical tube. The cell suspension is centrifuged at 400 x g for 5 minutes at 4°C, and the supernatant is discarded. The cells are resuspended in a volume equal to the original blood draw in PBS containing 1% bovine serum albumin and 0.5% EDTA (staining buffer). Viable cells are then counted using a hemocytometer. The cell suspension is centrifuged at 400 x g for 5 minutes at 4°C, the supernatant is discarded, and the cells are resuspended in staining buffer at approximately 10 cells per mL. 7 Resuspend to a cell concentration of 1000 and transfer 1 mL aliquots to fresh tubes.

[0187] The following antibodies are added to the resuspended cells: FITC-conjugated anti-CD14; PE-conjugated anti-HLA-DR; and APC-conjugated anti-CD3, anti-CD19, and anti-CD56. Control samples include unstained cells and stained cells in which one of each set of fluorochrome antibodies has been omitted. The cells are protected from light to minimize exposure and allowed to stand at room temperature for 20 minutes. The stained cells are washed twice in staining buffer by centrifugation at 400 x g for 5 minutes at 4°C, the supernatant discarded, and resuspended in an equal volume of staining buffer. The stained cells are then transferred to polypropylene tubes for use in the flow cytometer.

[0188] Flow cytometry was performed on a Cytomics FC500 flow cytometer, which automates flow cytometry data acquisition for each tube. After automated measurements, samples were corrected for both background fluorescence (using unstained samples) and fluorochrome compensation (using individually depleted fluorochrome samples). CD14-positive, HLA-DR-high, and CD16-negative cells were identified by CD14-positive, HLA-DR-high expression, and CD16-, CD3-, CD19-, and CD56-negative expression. Peripheral blood mononuclear cells were identified by CD3-, CD19-, and CD56-positive expression. These values ​​were used to calculate the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells among total peripheral blood mononuclear cells. In this situation, if the patient has a percentage of CD14 positive, HLA-DR-high, and CD16 negative cells of at least 5% to 100%, and indicates the presence of a high number of CD14 positive, HLA-DR-high, and CD16 negative cells, the patient is selected for combination therapy with entinostat and pembrolizumab. Example 2. Selection of Melanoma Patients for Entinostat Combination Therapy with Pembrolizumab

[0189] To select patients for combination treatment with entinostat and pembrolizumab, peripheral blood samples were collected from patients. Patients were diagnosed with melanoma that progressed during or failed to respond to anti-PD-1 or anti-PD-L1 treatment. A 5 milliliter (mL) peripheral blood sample was collected in an EDTA blood collection tube and rapidly chilled on ice. The blood sample was transferred to a conical tube and diluted with 15 mL of red blood cell lysis buffer and incubated at room temperature for 10 minutes. The red blood cell lysate was quenched by diluting with 30 mL of phosphate-buffered saline (PBS). The cell suspension was centrifuged at 400 × g for 5 minutes at 4°C, and the supernatant was discarded. The pellet was resuspended in 5 mL of PBS and transferred to a new conical tube. The resuspended sample was sedimented with 5 mL of Ficoll®. The cells are centrifuged at 400 x g for 20 minutes with the centrifuge brake off. The nucleated cells are collected at the interface between the PBS and Ficoll® layers and placed in a new conical tube.

[0190] The cells are washed by adding a volume equal to the original blood draw to the pellet in a new conical tube. The cell suspension is centrifuged at 400 x g for 5 minutes at 4°C, and the supernatant is discarded. The cells are resuspended in a volume equal to the original blood draw in PBS containing 1% bovine serum albumin and 0.5% EDTA (staining buffer). Viable cells are then counted using a hemocytometer. The cell suspension is centrifuged at 400 x g for 5 minutes at 4°C, the supernatant is discarded, and the cells are resuspended in staining buffer at approximately 10 cells per mL. 7 Resuspend to a cell concentration of 1000 and transfer 1 mL aliquots to fresh tubes.

[0191] The following antibodies are added to the resuspended cells: FITC-conjugated anti-CD14; PE-conjugated anti-HLA-DR; and APC-conjugated anti-CD3, anti-CD19, and anti-CD56. Control samples include unstained cells and stained cells in which one of each set of fluorochrome antibodies has been omitted. The cells are protected from light to minimize exposure and allowed to stand at room temperature for 20 minutes. The stained cells are washed twice in staining buffer by centrifugation at 400 x g for 5 minutes at 4°C, the supernatant discarded, and resuspended in an equal volume of staining buffer. The stained cells are then transferred to polypropylene tubes for use in the flow cytometer.

[0192] Flow cytometry was performed on a Cytomics FC500 flow cytometer, which automates flow cytometry data acquisition for each tube. After automated measurements, samples were corrected for both background fluorescence (using unstained samples) and fluorochrome compensation (using individually depleted fluorochrome samples). CD14-positive, HLA-DR-high, and CD16-negative cells were identified by CD14-positive, HLA-DR-high expression, and CD16-, CD3-, CD19-, and CD56-negative expression. Peripheral blood mononuclear cells were identified by CD3-, CD19-, and CD56-positive expression. These values ​​were used to calculate the percentage of CD14-positive, HLA-DR-high, and CD16-negative cells among total peripheral blood mononuclear cells. In this situation, if the patient has a percentage of CD14 positive, HLA-DR-high, and CD16 negative cells of at least 5% to 100%, and indicates the presence of a high number of CD14 positive, HLA-DR-high, and CD16 negative cells, the patient is selected for combination therapy with entinostat and pembrolizumab.

[0193] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the invention described herein. The scope of the invention is, therefore, indicated by the appended claims, rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. 1. A method for selecting a patient for combination therapy comprising an HDAC inhibitor and a second therapeutic agent, comprising: providing a peripheral blood sample obtained from said patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14 positive, HLA-DR-high, and / or CD16 negative cells relative to total peripheral blood mononuclear cells is greater than a predetermined percentage.

2. 1. A method for providing a prognosis for cancer in a patient, comprising: providing a peripheral blood sample from said patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; Enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and further comprising: administering to the patient a combination therapy comprising an HDAC inhibitor and a second therapeutic agent if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total peripheral blood mononuclear cells is greater than a predetermined percentage; A method comprising:

3. The method of claims 1-2, wherein the patient has deteriorated during prior therapy with an anti-PD-1 antibody, an anti-PD-L1 antibody, a CTLA4 blocking antibody, or any combination thereof.

4. 4. The method of claim 3, wherein the patient was previously considered non-responsive to at least one prior therapy.

5. 5. The method of claim 1, comprising counting the number of CD14-positive and HLA-DR-high, CD14-positive and CD16-negative, or HLA-DR-high and CD16-negative cells in a peripheral blood sample.

6. The method according to any one of claims 1 to 5, comprising measuring the number of CD14-positive, HLA-DR-high and CD16-negative cells in a peripheral blood sample.

7. The method of any one of claims 1 to 6, wherein the peripheral blood sample is treated with an anticoagulant.

8. 8. The method of claim 7, wherein the anticoagulant is EDTA or heparin.

9. The method of any one of claims 1 to 8, wherein the predetermined percentage is at least about 5%.

10. The method of any one of claims 1 to 9, wherein the predetermined percentage is at least about 10%.

11. The method of any one of claims 1 to 10, wherein the predetermined percentage is at least about 15%.

12. The method of any one of claims 1 to 11, wherein the predetermined percentage is at least about 20%.

13. The method of any one of claims 1 to 12, wherein the predetermined percentage is at least about 25%.

14. The method of any one of claims 1 to 13, wherein the predetermined percentage is at least about 30%.

15. The method of any one of claims 1 to 14, wherein the predetermined percentage is at least about 35%.

16. The method of any one of claims 1 to 15, wherein the predetermined percentage is at least about 40%.

17. The method of any one of claims 1 to 16, wherein the predetermined percentage is at least about 45%.

18. The method of any one of claims 1 to 17, wherein the predetermined percentage is at least about 50%.

19. 19. The method of any one of claims 1 to 18, wherein the HDAC inhibitor is entinostat.

20. 20. The method of claim 19, wherein the entinostat is administered orally.

21. 21. The method of any one of claims 19 to 20, wherein the entinostat is administered first.

22. 22. The method of any one of claims 19 to 21, wherein the entinostat is administered weekly.

23. 23. The method of any one of claims 19 to 22, wherein the entinostat is administered every two weeks.

24. 24. The method of any one of claims 19 to 23, wherein the entinostat is administered at a dose of 3 mg once per week for a treatment cycle.

25. 25. The method of any one of claims 19 to 24, wherein the entinostat is administered at a dose of 5 mg once per week during a treatment cycle.

26. 20. The method of claim 19, wherein the entinostat is administered at a dose of 5 mg.

27. 27. The method of any one of claims 1 to 26, wherein the second therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, a CTLA4 blocking antibody, or a combination thereof.

28. 28. The method of any one of claims 1 to 27, wherein the second therapeutic agent is an anti-PD-1 antibody.

29. 29. The method of claim 28, wherein the anti-PD-1 antibody is pembrolizumab.

30. 29. The method of claim 28, wherein the anti-PD-1 antibody is nivolumab.

31. The method of any one of claims 1 to 27, wherein the second therapeutic agent is an anti-PD-L1 antibody.

32. 32. The method of claim 31, wherein the anti-PD-L1 antibody is MPDL3280A.

33. 32. The method of claim 31, wherein the anti-PD-L1 antibody is avelumab.

34. 28. The method of any one of claims 1 to 27, wherein the second therapeutic agent is a CTLA4 blocking antibody.

35. The method of any one of claims 1 to 34, wherein the cancer is lung cancer.

36. 36. The method of claim 35, wherein the lung cancer is non-small cell lung cancer, squamous cell carcinoma, or large cell carcinoma.

37. The method of any one of claims 1 to 34, wherein the cancer is melanoma.

38. 38. The method of claim 37, wherein the melanoma is metastatic melanoma.

39. The method of any one of claims 1 to 34, wherein the cancer is breast cancer.

40. 40. The method of claim 39, wherein the breast cancer is triple-negative breast cancer.

41. 40. The method of claim 39, wherein the breast cancer is hormone receptor positive breast cancer.

42. The method of any one of claims 1 to 34, wherein the cancer is ovarian cancer.

43. 43. The method of any one of claims 1 to 42, wherein the entinostat and the second therapeutic agent are administered sequentially in any order or simultaneously.

44. 28. The method of claim 27, wherein the anti-PD-1 antibody, anti-PD-L1 antibody, or CTLA4 blocking antibody is administered by infusion.

45. 45. The method of any one of claims 1 to 44, wherein the patient has received at least one round of prior therapy.

46. 45. The method of any one of claims 1 to 44, wherein the patient has received at least three rounds of prior therapy.

47. 1. A method for selecting a patient for combination therapy comprising entinostat and a second therapeutic agent, comprising: providing a peripheral blood sample obtained from said patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14 positive, HLA-DR-high, and / or CD16 negative cells relative to total peripheral blood mononuclear cells is greater than a predetermined percentage.

48. 1. A method for providing a prognosis for cancer in a patient, comprising: providing a peripheral blood sample from said patient diagnosed with cancer; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; Enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and further comprising: administering to the patient a combination therapy comprising entinostat and a second therapeutic agent if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total peripheral blood mononuclear cells is greater than a predetermined percentage; A method comprising:

49. 1. A method for selecting a patient for combination therapy comprising entinostat and a second therapeutic agent, comprising: providing a peripheral blood sample from said patient diagnosed with non-small cell lung cancer and / or melanoma and who has progressed during and / or been deemed unresponsive to prior PD-1 or PD-L1 therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and administering the combination therapy if the percentage of CD14 positive, HLA-DR-high, and / or CD16 negative cells relative to total peripheral blood mononuclear cells is greater than a predetermined percentage.

50. 1. A method for providing a prognosis for cancer in a patient, comprising: providing a peripheral blood sample from said patient diagnosed with non-small cell lung cancer and / or melanoma and who has progressed during and / or been deemed unresponsive to prior PD-1 or PD-L1 therapy; counting the number of CD14-positive, HLA-DR-high, and / or CD16-negative cells in the peripheral blood sample; Enumerating the number of total peripheral blood mononuclear cells in the peripheral blood sample; and further comprising: administering to the patient a combination therapy comprising entinostat and a second therapeutic agent if the percentage of CD14-positive, HLA-DR-high, and / or CD16-negative cells relative to total peripheral blood mononuclear cells is greater than a predetermined percentage; A method comprising:

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