Combining Glutamate Modulating Agents with Immunotherapy to Treat Cancer - Patent application

Abstract

Pharmaceutical combinations for the treatment of cancer are provided. [Solution] Provided is a combination pharmaceutical comprising a glutamate modulator and an immunotherapeutic anticancer agent, wherein the glutamate modulator is, for example, one having the following formula, or an enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, or complex thereof, and the immunotherapeutic anticancer agent is a combination of pembrolizumab and nivolumab. JPEG2022191256000015.jpg2385

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 339,433, filed May 20, 2016.

[0002] FIELD OF THEINVENTION The present invention relates to the use of glutamate modulating agents and immunotherapeutic anti-cancer agents in the treatment of cancer. [Background technology]

[0003] Glutamate is the major excitatory neurotransmitter responsible for regulating signal transduction in normal brain function. Research on glutamate signal transduction has focused primarily on the central nervous system (CNS), but other studies have shed light on their functional role in peripheral tissues. For example, see Non-Patent Document 1 and Non-Patent Document 2.

[0004] Glutamate can exert its signaling potential by acting on glutamate receptors on the cell surface. Glutamate receptors exist as ionotropic receptors (iGluRs) or metabotropic glutamate receptors (mGluRs). iGluRs are ligand-gated ion channels and include N-methyl-d-aspartate (NMDA) receptors and non-NMDA receptors [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] (iGluR1-4) and the kainate (KA) subfamily (iGluR5-7, KA1 and KA2). mGluRs are domain receptors that mediate their signals by coupling with guanosine triphosphate (GTP)-binding proteins (G proteins) to stimulate second messengers such as inositol 1,4,5-triphosphate (IP3), diacylglycerol (DAG), and cyclic adenosine monophosphate (cAMP). Various mGluR subtypes have been identified and classified according to their sequence homology, pharmacological responses and intracellular second messengers. Upon ligand binding, receptor type I, consisting of mGluR1 and mGluR5, binds G q Type II contains mGluR2 and mGluR3, and type III contains mGluR4, mGluR6, mGluR7, and mGluR8. Both types II and III are G i / o It negatively couples with adenyl cyclase via , resulting in the formation of cAMP.

[0005] Glutamate can also be transported. Glutamate transporters have been cloned from the mammalian central nervous system. Two are expressed primarily in glia [glial glutamate-aspartate transporter (GLAST) and glial glutamate transporter (GLT)], and three are expressed in neurons [EAAC1, excitatory amino acid transporter (EAAT) 4, and EAAT5]. See, for example, Non-Patent Document 4. More information on glutamate transport can be found in the literature. See, for example, Non-Patent Document 5.

[0006] Glutamate can also be metabolized. Glutamate metabolic reactions can be catalyzed by enzymes that are regulated by activators and inhibitors. For example, the conversion of L-glutamate to N-acetyl-L-glutamate in the presence of N-acetylglutamate synthase (NAGS) is activated by L-arginine and inhibited by succinate, coenzyme A, N-acetyl-L-aspartate and N-acetyl-L-glutamate. See, for example, Non-Patent Document 6. Similarly, the conversion of glutamine to glutamate can be catalyzed by enzymes including glutaminase (GLS / GLS2), phosphoribosyl pyrophosphate amidotransferase (PPAT) and glutamine-fructose-6-phosphate transaminase (GFPT1 and GFPT2). See, for example, Non-Patent Document 7 and Non-Patent Document 8.

[0007] Glutamine, which functions as a precursor of glutamic acid, is known to protect the body against nutrient depletion, oxidative stress and tumor stress. For example, see Non-Patent Document 9. Reports have shown that ammonia released from glutamine by the action of glutaminase regulates autophagy in cancer cells through a process known as glutaminolysis. For example, see Non-Patent Document 10. In cancer cells, glutaminolysis can serve as fuel for cell growth and proliferation through the synthesis of fatty acids, nucleotides and amino acids. For example, see Non-Patent Document 11. Expression of glutaminase can be regulated by the transcription factor c-Myc, which in turn regulates cell growth and cell death of human prostate cancer cells. For example, see Non-Patent Document 12. It has been shown that in brain tumors such as gliomas, glioma cells can release excess glutamic acid into the extracellular space, causing tumor-associated epilepsy or seizures. For example, see Non-Patent Document 13. It has also been suggested that glutamic acid release promotes cell proliferation, cell invasion and tumor necrosis in glioblastoma. See, e.g., J. Am. 1999, 144: 1311-1315, 2002. Further information regarding glutamate and glutamine metabolism can be found in the literature, see, e.g., J. Am. 1999, 144: 1311-1315, 2002 and J. Am. 1999, 144: 1311-1315, 2002.

[0008] Riluzole (6-(trifluoromethoxy)benzothiazol-2-amine) is a pharmaceutical agent used to treat amyotrophic lateral sclerosis (ALS). Recently, riluzole has been shown to have other clinical usefulness. For example, oral administration of riluzole twice daily at a total dose of 100 mg / day can alleviate or treat psychoneurological symptoms and disorders such as mood disorders, anxiety, refractory depression, and obsessive-compulsive anxiety. See, for example, Non-Patent Document 17. There are also some indications that riluzole may have anticancer effects. See, for example, Non-Patent Document 18.

[0009] Human cancers harbor numerous genetic and epigenetic mutations and produce neoantigens that may be recognized by the immune system. See, for example, Non-Patent Document 19. The adaptive immune system, consisting of T and B lymphocytes, has a strong anticancer potential, with a broad ability to respond to various tumor antigens and exquisite specificity. The immune system also shows considerable plasticity and memory elements. By exploiting these properties of the adaptive immune system, immunotherapy is unique among current cancer treatment modalities.

[0010] Cancer immunotherapy includes approaches to enhance antitumor immune responses by adoptive transfer of activated effector cells, immunization against relevant antigens, or provision of non-specific immunostimulants such as cytokines. Cancer immunotherapy also includes immune checkpoint pathway inhibitors, which provide novel immunotherapeutic approaches for cancer treatment, including inhibitors that target the programmed death-1 (PD-1) receptor to block the inhibitory PD-1 / PD-1 ligand pathway and the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor.

[0011] PD-1 is an important immune checkpoint receptor expressed by activated T and B cells and mediates immune suppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1 and BTLA. Two cell surface glycoprotein ligands of PD-1, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2), have been identified, which are expressed on antigen-presenting cells and many human cancers, and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1. Inhibition of PD-1 / PD-L1 interaction mediates potent antitumor activity in preclinical models (see, for example, Patent Documents 1 and 2), and the use of antibody inhibitors of PD-1 / PD-L1 interaction for cancer treatment has been investigated in clinical trials. See, for example, Non-Patent Document 20; Non-Patent Document 21.

[0012] Nivolumab (trade name: Opdivo TMPembrolizumab (marketed under the trade name "KEYTRUDA") by Bristol-Myers Squibb Company (Princeton, NJ, USA) and also known as 5C4, BMS-936558, MDX-1106 or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that blocks downregulation of antitumor T cell function by selectively preventing interaction with PD-1 ligands (PD-L1 and PD-L2). See, e.g., U.S. Pat. No. 5,393,621; see also U.S. Pat. No. 5,433,366; U.S. Pat. No. 5,521,621; see also U.S. Pat. No. 5,433,366. TM Lambrolizumab (also known as MK-3475 and lambrolizumab, marketed by Merck & Co., Inc. (Whitehouse Station, NJ, USA) under the trademark "Pembrolizumab" (Pembrolizumab) is a humanized monoclonal IgG4 antibody against the human cell surface receptor PD-1. Pembrolizumab is described, for example, in U.S. Pat. No. 5,393,311 and U.S. Pat. No. 5,493,311; see also U.S. Pat. No. 5,521,636.

[0013] Ipilimumab (trade name: YERVOY TM Ipilimumab (marketed under the title "TNF-α agonist and agonist agonist agonist agonist") by Bristol-Myers Squibb Company (Princeton, NJ, USA) is a fully human IgG1 monoclonal antibody that inhibits the binding of CTLA-4 to its B7 ligand, stimulating T cell activation and improving overall survival in patients with advanced melanoma. Ipilimumab is described, for example, in US Pat. No. 5,333,663; see also US Pat. No. 5,333,663.

[0014] Examples of other therapeutic approaches to cancer using immune-targeted anticancer agents include other antibodies targeting various receptors, as well as peptides, proteins, small molecules, adjuvants, cytokines, oncolytic viruses, vaccines, bispecific molecules, and cellular therapeutics. See, for example, Non-Patent Document 26 and Non-Patent Document 27.

[0015] Despite the benefits that patients have received through immunotherapeutic cancer treatment, improvements are desired, for example, improvements in patient response in areas such as overall survival, quality of life, overall response rate, duration of response, progression free survival, patient reported outcome, minimal residual disease, or immune response. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] U.S. Pat. No. 8,008,449 [Patent Document 2] U.S. Pat. No. 7,943,743 [Patent Document 3] U.S. Pat. No. 8,354,509 [Patent Document 4] U.S. Pat. No. 8,900,587 [Patent Document 5] U.S. Patent No. 6,984,720 [Non-patent literature]

[0017] [Non-Patent Document 1] Skerry T, Genever P, Glutamate signaling in non-neuronal tissues. Trends Pharmacol Sci 2001, 22:174-181 [Non-Patent Document 2] Frati C, Marchese C, Fisichella G, Copani A, Nasca MR, Storto M, Nicoletti F, Expression of functional mGlu5 metabotropic glutamate receptors in humanmelanocytes. J Cell Physiol 2000, 183:364–372

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[0018] The present invention is directed to combination immunotherapy with glutamate modulators and immunotherapeutic agents for the treatment of diseases, particularly cancer. Thanks to the present invention, it may now be possible to provide more effective immuno-oncology treatments to patients. Patients may experience improved response in one or more areas, including, for example, overall survival, quality of life, overall response rate, duration of response, progression-free survival, patient-reported outcomes, minimal residual disease, or immune response.

[0019] In one aspect of the present invention, there is provided a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a glutamate modulating agent and an immunotherapeutic anti-cancer agent.

[0020] In one embodiment, the glutamate modulator is an agent that promotes the regulation, control, attenuation or enhancement of (i) ionotropic glutamate receptors; (ii) metabotropic glutamate receptors; or (iii) glutamate transporters. In one embodiment, the glutamate modulator is an agent that inhibits glutamate release. In one embodiment, the glutamate modulator is an agent that regulates, regulates, attenuates or enhances glutamate or glutamine metabolism. In one embodiment, the ionotropic glutamate receptor is selected from NMDA, AMPA and kainate. In one embodiment, the metabotropic glutamate receptor is one or more of type 1 receptors selected from mGluR1 and mGluR5; type II receptors selected from mGluR2 and mGluR3; or type III receptors selected from mGluR4, mGluR6, mGluR7 and mGluR8. In one embodiment, the glutamate transporter is expressed in glia or neurons.

[0021] In one embodiment of the invention, the glutamate modulating agent is selected from riluzole, memantine, n-acetylcysteine, amantadine, topiramate, pregabalin, lamotrigine, ketamine, s-ketamine, AZD8108, AZD6765 (lanicemine), BHV-4157 (trigriluzole), dextromethorphan, AV-101, CERC-301, GLY-13, and pharma- ceutically acceptable salts, prodrugs or analogs thereof.

[0022] In one embodiment of the present invention, the immunotherapy anticancer agent is selected from antibodies, peptides, proteins, small molecules, adjuvants, cytokines, oncolytic viruses, vaccines, bispecific molecules and cellular therapeutics. In one embodiment, the immunotherapy anticancer agent is a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitor of a checkpoint receptor selected from PD-1, PD-L1 and CTLA-4. In one embodiment, the inhibitor of PD-1 is nivolumab, pembrolizumab and pidil. R Zumab (pidil i zumab). In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody selected from BMS-936559, durvalumab, atezolizumab, avelumab, and MDX-1105. In one embodiment, the PD-L1 inhibitor is a peptide. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from ipilimumab and tremelimumab.

[0023] In one embodiment of the present invention, the glutamate modulating agent and the immunotherapeutic anti-cancer agent provide a mouse survival ratio (MSR) at day 60 of at least 2.0. 60 )

[0024] In one embodiment of the present invention, a method of modulating glutamate in a patient undergoing treatment with an immunotherapeutic anti-cancer agent is provided, comprising contacting a glutamate receptor or glutamate transporter in the patient with a glutamate modulating agent proximal to the treatment with the immunotherapeutic anti-cancer agent. In one embodiment, the glutamate modulating agent is riluzole. In one embodiment, riluzole is administered intravenously, intramuscularly, parenterally, sublingually, nasally, or orally. In one embodiment, riluzole is administered in the form of a prodrug. In one embodiment, the prodrug has the following formula: [ka] has.

[0025] In one embodiment, contacting the glutamate receptor or transporter with the glutamate modulator occurs prior to, concurrently with, or after treatment with an immunotherapeutic anticancer agent. In one embodiment, close to is within one week of treatment with an immunotherapeutic anticancer agent.

[0026] In one embodiment of the present invention, a method of sensitizing a patient suffering from cancer undergoing treatment with an immunotherapeutic anticancer agent is provided, comprising administering to the patient a therapeutically effective amount of a glutamate modulating agent proximal to the treatment with the immunotherapeutic anticancer agent. In one embodiment, the sensitization promotes an enhanced antitumor effect. In one embodiment, the enhanced antitumor effect is measured by an increased objective response rate or an increased duration of response in the patient.

[0027] In one embodiment, the enhancement of antitumor effect promotes the increase of overall survival of patients.In one embodiment, the patient shows an overall survival of at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after the first administration of immunotherapy anticancer agent.In one embodiment, the overall survival is at least about 1.1 times, at least about 1.2 times, at least about 1.3 times, at least about 1.4 times, at least about 1.5 times, at least about 2.0 times, at least about 3.0 times, or at least about 3.0 times that of the overall survival of patients treated with a therapeutically effective amount of immunotherapy anticancer agent but not treated with glutamate modulating agent.

[0028] In one embodiment of the present invention, a method for improving the response in a patient suffering from cancer undergoing treatment with an immunotherapy anticancer agent is provided, comprising administering to a patient in need of the improvement an effective amount of an immunotherapy anticancer agent and riluzole or a prodrug thereof.In one embodiment, the immunotherapy anticancer agent is a checkpoint inhibitor.In one embodiment, the checkpoint inhibitor is an inhibitor of a checkpoint receptor selected from PD-1, PD-L1 and CTLA-4.In one embodiment, the patient is additionally treated with an antibody selected from anti-LAG3 antibody, anti-CD137 antibody, anti-KIR antibody, anti-TGFp antibody, anti-IL-10 antibody, anti-B7-H4 antibody, anti-Fas ligand antibody, anti-CXCR4 antibody, anti-mesothelin antibody, anti-CD20 antibody, anti-CD27 antibody, anti-GITR antibody, anti-OX40 antibody, or a combination thereof. In one embodiment, the patient is additionally treated with radiation therapy, chemotherapy, a vaccine, a cytokine, a tyrosine kinase inhibitor, an anti-VEGF inhibitor, an IDO inhibitor, an IDO1 inhibitor, a TGF-β inhibitor, or a combination thereof.

[0029] In one embodiment of the invention, the cancer is melanoma cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (acute myeloid leukemia, chronic ... The cancer is selected from: myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of early childhood, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, CNS neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer (including cancer induced by asbestos), and combinations thereof.

[0030] In one embodiment, the improved response is one or more of overall survival, quality of life, overall response rate, duration of response, progression-free survival, patient-reported outcome, minimal residual disease, or immune response.

[0031] In one embodiment of the invention, there is provided a kit for treating a patient suffering from cancer, comprising: (a) an immunotherapeutic anticancer agent; and (b) instructions for administering an immunotherapeutic anti-cancer agent in conjunction with a glutamate modulating agent in the methods of the invention; In one embodiment, the immunotherapy anticancer agent is selected from nivolumab, pembrolizumab, pidilzumab, durvalumab, atezolizumab, avelumab, ipilimumab, and tremelimumab.

[0032] In one embodiment of the invention, there is provided a kit for treating a patient suffering from cancer, comprising: (a) a glutamate modulator; and (b) instructions for administering a glutamate modulating agent in conjunction with an immunotherapeutic anticancer agent in the methods of the invention; In one embodiment, the glutamate modulating agent is riluzole or a prodrug thereof.

[0033] These and other aspects and features of the present invention will become apparent from the drawings and detailed description. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 illustrates the results of the study described in Example 1 showing survival in a glioblastoma animal model testing a riluzole prodrug (BHV-4157), an anti-PD-1 antibody, alone and in combination, along with a control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Detailed Description of the Invention The following detailed description is provided to help those skilled in the art to carry out the present invention.Those skilled in the art can make modifications and changes to the embodiments described herein without departing from the spirit or scope of the present disclosure.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present disclosure belongs.The terms used herein are only for describing specific embodiments and are not intended to be limiting.

[0036] As used in this application, unless expressly stated otherwise herein, the following terms shall each have the meaning set forth below. Additional definitions are set forth throughout this application. If a term is not specifically defined herein, the term is given its art-recognized meaning by those of ordinary skill in the art applying the term in the context of its use in describing the present invention.

[0037] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an element" means one element or more than one element.

[0038] The term "about" refers to a value or composition within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., the limits of the measurement system. For example, "about" can mean within one or more standard deviations, as is customary in the art. Alternatively, "about" can mean within a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can encompass numbers between 2.7 mg and 3.3 mg (at 10%) or 2.4 mg and 3.6 mg (at 20%). Furthermore, particularly with respect to biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. When a particular value or composition is described in the present application and claims, unless otherwise indicated, the meaning of "about" should be assumed to be within an acceptable error range for this particular value or composition.

[0039] The term "ALS" refers to amyotrophic lateral sclerosis.

[0040] The term "administering" refers to the physical introduction of a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. For example, the route of administration of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) can include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration (e.g., by injection or infusion). As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral administration and topical administration (usually by injection), including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In some embodiments, the immunotherapy anticancer agent, such as immune checkpoint inhibitor, is administered by non-parenteral route, and in some embodiments, is administered orally.The typical administration route of glutamate modulating agent, such as riluzole, can include buccal, intranasal, ocular, oral, osmotic, parenteral, rectal, sublingual, topical, transdermal, or vaginal.Administration can also be, for example, one time, multiple times, and / or one or more extended periods, and can be therapeutically effective or subtherapeutic doses.

[0041] The term "anti-antigen" antibody refers to an antibody that specifically binds to an antigen, but is not limited to this. For example, an anti-PD-1 antibody specifically binds to PD-1, and an anti-CTLA-4 antibody specifically binds to CTLA-4.

[0042] An "antigen-binding portion" of an antibody (also referred to as an "antigen-binding fragment") refers to, but is not limited to, one or more fragments of an antibody that retain the ability to specifically bind to the antigen bound by the whole antibody.

[0043] The term "antibody" (Ab) refers to, but is not limited to, a glycoprotein immunoglobulin or antigen-binding portion thereof that specifically binds to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain contains a heavy chain variable region (herein referred to as V H The heavy chain constant region comprises three constant domains, C H1 , C H2 and C H3 Each light chain comprises a light chain variable region (referred to herein as V L The light chain constant region comprises one constant domain, C L Includes: V H Area and V L The regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), separated by more conserved regions, called framework regions (FRs). H and V L comprises three CDRs and four FRs arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0044] Immunoglobulins may be derived from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those skilled in the art, including but not limited to human IgG1, IgG2, IgG3 and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by heavy chain constant region genes, but is not limited thereto. In certain embodiments, one or more amino acids of an isotype may be mutated to alter effector function. The term "antibody" includes, by way of example, both naturally occurring and non-naturally occurring Abs; monoclonal and polyclonal Abs; chimeric and humanized Abs; human or non-human Abs; fully synthetic Abs; and single chain antibodies. Non-human antibodies may be humanized by recombinant methods to reduce their immunogenicity in humans. Unless expressly stated, and unless the context indicates otherwise, the term "antibody" also includes antigen-binding fragments or portions of any of the above immunoglobulins, including monovalent and divalent fragments or portions, and single-chain antibodies.

[0045] The term "AUC" (area under the curve) refers to the total amount of drug absorbed or exposed to a subject. In general, AUC can be obtained from mathematical methods in the plot of drug concentration in a subject over time until the concentration becomes negligible. The term "AUC" (area under the curve) can also refer to the partial AUC at a particular time interval (as in the case of sublingual absorption, which will increase the AUC at earlier time intervals).

[0046] The term "cancer" refers to a broad group of different diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth leads to the formation of malignant tumors that can invade nearby tissues and metastasize to distant parts of the body through the lymphatic system or bloodstream. "Cancer" encompasses primary cancers, metastatic cancers, and recurrent cancers, as well as precancerous conditions, i.e., conditions of abnormal morphology of cells that are associated with an increased risk of cancer. The term "cancer" includes, but is not limited to, the following proliferative disorders: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, childhood cancer, AIDS-related cancer, Kaposi's sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, bladder cancer, bone cancer, Ewing's sarcoma family of tumors, osteosarcoma and malignant fibrous histiocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, embryonal tumor, germ cell tumor, craniopharyngioma, ependymoma, breast cancer. , bronchial carcinoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, carcinoid tumors, gastrointestinal cancer, cardiac tumors, primary lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides and Sézary syndrome, ductal carcinoma in situ (DCIS), germinoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, malignant fibrous histiocytoma of bone and osteosarcoma (fibrous sarcoma) Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder cancer, Gastric cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Germ cell tumor, Ovarian, Testicular, Gestational trophoblastic disease, Glioma, Hairy cell leukemia, Head and neck cancer, Hepatocellular (liver) carcinoma, Langerhans cell histiocytosis,Langerhans Cell), Hodgkin's Lymphoma, Hypopharyngeal Cancer, Islet Cell Tumor, Pancreatic Neuroendocrine Tumor, Kaposi's Sarcoma, Kidney, Renal Cell, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (Chronic Lymphocytic (CLL), Chronic Myeloid (CML), Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lung Cancer (Non-Small Cell, Small Cell), Lymphoma (Hodgkin, Non-Hodgkin), Macroglobulinemia (Waldenstrom), Male Breast Cancer, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma / Plasma Cell Neoplasms, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic / Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML) Myeloma, Multiple, Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin's Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Low Malignant Potential Tumors Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumor (Islet Cell Tumor), Papilloma, Paraganglioma, Paranasal Sinus and Nasal Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasmacytoma / Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary CNS Lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer,Renal Pelvis and Ureter, Transitional Cell Carcinoma, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Carcinoma, Uterine Rhabdomyosarcoma, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Gastric Cancer, T-Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Unknown Primary, Ureter and Renal Pelvis, Transitional Cell Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom's Macroglobulinemia, and Wilms' Tumor.

[0047] The term "chimeric antibody" refers to, but is not limited to, an antibody whose variable region is derived from one species and whose constant region is derived from another species, such as an antibody whose variable region is derived from a mouse antibody and whose constant region is derived from a human antibody.

[0048] The term "Cmax" refers to the maximum concentration of drug in a subject's blood, serum, or a particular compartment or test area between the administration of the first and second doses. The term Cmax can also refer to the dose normalized ratio, if specified.

[0049] The term "cytotoxic T-lymphocyte antigen 4" (CTLA-4) refers to an immunoinhibitory receptor belonging to the CD28 family. CTLA-4 is expressed exclusively on T cells in vivo and binds to two ligands, CD80 and CD86 (also called B7-1 and B7-2, respectively). The term "CTLA-4" includes human CTLA-4 (hCTLA-4), variants, isoforms and species homologs of hCTLA-4, and analogs that share at least one common epitope with hCTLA-4. The complete hCTLA-4 sequence can be found under GenBank Accession No. AAB59385.

[0050] The term "dosing interval" refers to the amount of time that elapses between multiple doses of the formulations described herein being administered to a subject. Thus, the dosing interval can be expressed as a range.

[0051] The term "dosage frequency" refers to the number of times that multiple doses of the formulations described herein are administered over a period of time. The administration frequency can be expressed as the number of administrations per period of time, for example, once per week or once every two weeks.

[0052] The term "effective amount" refers to an amount sufficient to produce an intended result. The effective amount varies depending on the subject and condition being treated, the severity of the affliction, and the method of administration, and can be routinely determined by one of ordinary skill in the art.

[0053] The term "flat dose" refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, a flat dose is not provided as a mg / kg dose, but rather as an absolute dose of an agent (e.g., an anti-PD-1 antibody). For example, a 60 kg human and a 100 kg human receive the same dose of an antibody (e.g., 240 mg of an anti-PD-1 antibody).

[0054] The term "fixed dose" with respect to the compositions of the invention refers to the presence of two different therapeutic agents in a single composition in a specific (fixed) ratio to each other in the composition. In some embodiments, the fixed dose is based on the weight (e.g., mg) of the therapeutic agent. In certain embodiments, the fixed dose is based on the concentration (e.g., mg / ml) of the two antibodies. In some embodiments, the ratio is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about The ratio may be 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1. For example, a 3:1 ratio of first and second antibodies can mean that a vial can contain about 240 mg of the first antibody and 80 mg of the second antibody, or about 3 mg / ml of the first antibody and 1 mg / ml of the second antibody.

[0055] The term "human antibody" (HuMAb) refers to, but is not limited to, an antibody having a variable region in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from a human germline immunoglobulin sequence. The human antibodies of the present invention can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms "human" antibody and "fully human" antibody are used interchangeably.

[0056] "Humanized antibody" refers to, but is not limited to, an antibody in which some, most, or all of the amino acids outside the CDR domains of a non-human antibody have been replaced with the corresponding amino acids from a human immunoglobulin. In one embodiment of a humanized form of an antibody, some, most, or all of the amino acids outside the CDR domains are replaced with amino acids from a human immunoglobulin, while some, most, or all of the amino acids within one or more CDR regions remain unchanged. Minor additions, deletions, insertions, substitutions, or modifications of amino acids are permitted as long as they do not eliminate the ability of the antibody to bind to a particular antigen. A "humanized" antibody retains the same antigen specificity as the original antibody.

[0057] The terms "immunotherapeutic anti-cancer agent", "immunotherapeutic agent" and "cancer immunotherapeutic agent" refer to agents that do not directly attack tumors, but instead activate the immune system through the subject's adaptive or innate immunity, and include a broad range of agents including, for example, antibodies, peptides, proteins, small molecules, adjuvants, cytokines, oncolytic viruses, vaccines, bispecific molecules and cellular therapeutic agents. Immunotherapeutic anti-cancer agents include agents that target the immune system to provide an anti-cancer therapeutic effect. Such targets and agents include, but are not limited to, anti-PD-1, anti-PD-L1, anti-CTLA4 or other immunotherapy or checkpoint inhibitor targets.

[0058] The term "immunotherapy" refers to the treatment of a subject afflicted with a disease or at risk of contracting a disease or suffering a recurrence of a disease by methods involving inducing, enhancing, suppressing, or otherwise altering the immune response.

[0059] The term "immune-related" response pattern refers to a clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce antitumor effects by inducing cancer-specific immune responses or by modifying natural immune responses. This response pattern is characterized by an initial increase in tumor burden or the appearance of new lesions, which is classified as disease progression in the evaluation of traditional chemotherapeutic agents and is synonymous with drug failure, followed by a beneficial therapeutic effect. Therefore, the proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.

[0060] The terms "in combination with" and "in conjunction with" refer to the administration of one treatment modality in addition to another treatment modality. Thus, "in conjunction with" or "in combination with" refers to the administration of one treatment modality to a subject before, during, or after the other treatment modality.

[0061] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities, including, but not limited to, (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species. Furthermore, an isolated antibody can be substantially free of other cellular material and / or chemicals.

[0062] The term "monoclonal antibody" ("mAb") refers to, but is not limited to, a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules which are essentially identical in primary sequence and which display a single binding specificity and affinity for a particular epitope. A mAb is an example of an isolated antibody. mAbs may be produced by hybridoma, recombinant, transgenic, or other techniques known to those of skill in the art.

[0063] "MSR x The term "mouse survival ratio", also referred to as "x" day after tumor implantation in mice, is calculated by dividing the survival rate of mice treated with (i) an immunotherapeutic anticancer agent plus a glutamate modulating agent by the survival rate of mice treated with (ii) an immunotherapeutic anticancer agent alone, according to the procedure described in Example 1. Thus, the MSR 60 refers to the mouse survival ratio 60 days after tumor implantation.

[0064] The term "pharmaceutical acceptable salt" refers to the salt form of one or more compounds or prodrugs described herein, which is provided to increase the solubility of the compound in the gastric or digestive fluids of the patient's digestive tract, so as to improve the dissolution and bioavailability of the compound.Pharmaceutical acceptable salts include those derived from inorganic and organic bases and acids, if applicable.Suitable salts include those derived from alkali metals such as potassium and sodium, and alkaline earth metals such as calcium and magnesium, and ammonium salts, among many acids and bases well known in the pharmaceutical arts.

[0065] "Programmed Death-1 (PD-1)" refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed primarily on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms and species homologs of hPD-1, and analogs that share at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank Accession No. U64863.

[0066] "Programmed death-ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands of PD-1 (the other is PD-L2) that downregulates T cell activation and cytokine secretion after binding to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, isoforms and species homologs of hPD-L1, and analogs that share at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank Accession No. Q9NZQ7.

[0067] The term "prodrug" refers to a precursor of a drug that can be administered in a modified or less active form. Prodrugs can be converted to an active drug form in a physiological environment by hydrolysis or other metabolic pathways. A discussion of prodrugs can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.

[0068] The term "sublingual administration" refers to a route of administration whereby a chemical or drug is placed under the subject's tongue.

[0069] The terms "subject" and "patient" refer to a human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates, such as non-human primates, sheep, dogs, and rodents, such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0070] The term "subtherapeutic dose" refers to a dose of a therapeutic agent (e.g., an antibody or glutamate modulating agent) that is lower than the usual or typical dose of the therapeutic agent when administered alone to treat a disease (e.g., cancer). In some embodiments of the invention, a therapeutically effective amount can include a subtherapeutic dose of either the immunotherapeutic anti-cancer agent or the glutamate modulating agent, or both.

[0071] The terms "therapeutically effective amount", "therapeutically effective dosage" and "therapeutically effective dose" of a drug (also sometimes referred to herein as "drug") refer to the amount of drug that, when used alone or in combination with other drugs, protects a subject from developing a disease or promotes disease regression as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or prevention of impairment or disability due to disease affliction. The ability of a drug to promote disease regression can be evaluated using various methods known to those skilled in the art, for example, by assaying the activity of the drug in human subjects in clinical trials, in animal model systems predicting efficacy in humans, or in in vitro assays. In certain embodiments, a therapeutically effective amount prevents the occurrence or recurrence of cancer overall. "Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer overall.

[0072] The term "Tmax" refers to the time or period after administration of a drug at which the maximum concentration (Cmax) is reached in a subject's blood, serum, specific compartment or test area.

[0073] The term "treatment" refers to the treatment of a condition or disease in a subject, and may include: (i) preventing the occurrence of the disease or condition in a subject who is predisposed to the disease but has not yet been diagnosed with the disease; (ii) inhibiting the disease or condition, i.e., arresting its occurrence; relieving the disease or condition, i.e., causing regression of the condition; or (iii) ameliorating or alleviating the condition caused by the disease, i.e., the symptoms of the disease. Treatment may be used in conjunction with other standard therapies or alone. Treatment or "treatment" of a subject also includes any type of intervention or process performed on a subject, or administration of a drug to a subject, for the purpose of ameliorating, alleviating, ameliorating, inhibiting, delaying, or preventing the onset, progression, occurrence, severity, or recurrence of symptoms, complications, or conditions, or biochemical signs associated with the disease.

[0074] The term "weight-based dose" refers to a dose administered to a patient calculated based on the patient's weight. For example, if a patient weighing 60 kg requires 3 mg / kg of anti-PD-1 antibody in combination with 1 mg / kg of anti-CTLA-4 antibody, the appropriate amount of anti-PD-1 antibody (i.e., 180 mg) and anti-CTLA-4 antibody (i.e., 60 mg) can be readily derived from a 3:1 ratio fixed dose formulation of anti-PD-1 antibody and anti-CTLA-4 antibody.

[0075] Immune checkpoint inhibitors are preferred for use according to the present invention. Preferred immune checkpoint inhibitors include anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody, or combinations thereof that provide desired efficacy and safety. In some embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody, or a portion thereof. In certain embodiments for treating human subjects, the antibody is a humanized antibody. In other embodiments for treating human subjects, the antibody is a human antibody. Antibodies of IgG1, IgG2, IgG3 or IgG4 isotypes can be used.

[0076] Preferred immune checkpoint inhibitors suitable for use according to the present invention include anti-PD-1 antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In the therapeutic methods described herein, the anti-PD-1 or anti-PD-L1 antibodies include antigen-binding moieties that bind to the PD-1 or PD-L1 receptor, respectively, and exhibit functional properties similar to those of the whole antibody in inhibiting ligand binding and upregulating the immune system. In one embodiment, the anti-PD-1 antibody is nivolumab. In one embodiment, the anti-PD-1 antibody is pembrolizumab. In another embodiment, the anti-PD-1 antibody is selected from human antibodies 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, which are described in U.S. Pat. No. 8,008,449. In yet other embodiments, the anti-PD-1 antibody is MEDI0608 (formerly AMP-514), AMP-224, or BGB-A317 or pidilizumab (CT-011).

[0077] Anti-PD-1 antibodies that can be used according to the present invention also include isolated antibodies that specifically bind to human PD-1 and cross-compete with another antibody (e.g., nivolumab) for binding to human PD-1. The ability of an antibody to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to this specific epitope region. These cross-competing antibodies are expected to have very similar functional properties to such antibodies (e.g., nivolumab) due to their binding to the same epitope region of PD-1. Cross-competing antibodies can be easily identified in standard PD-1 binding assays, such as Biacore analysis, ELISA assays, or flow cytometry, based on their cross-competing ability with such antibodies (e.g., nivolumab) (see, e.g., WO 2013 / 173223). For administration to human subjects, these cross-competing antibodies can be chimeric antibodies, or humanized or human antibodies. Such chimeric, humanized or human mAbs can be prepared and isolated by methods well known in the art.

[0078] Anti-PD-1 antibodies that can be used in the methods of the invention also include antigen-binding portions of the above antibodies. The antigen-binding function of an antibody can be performed by a fragment of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include: (i) V L Domain, V H Domain, C L Domain and C H1 (ii) a F(ab")2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a V H Domain and C H1 (iv) an Fd fragment consisting of the V domain of one arm of an antibody; L Domains and V H An example of such an Fv fragment is an Fv fragment consisting of a domain.

[0079] Antibodies of IgG1, IgG2, IgG3 or IgG4 isotypes may be used according to the invention. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof comprises a heavy chain constant region that is of human IgG1 or IgG4 isotype. In certain other embodiments, the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or antigen-binding portion thereof contains a S228P mutation that replaces a serine residue in the hinge region with a proline residue that is normally found at the corresponding position in IgG1 isotype antibodies. This mutation present in nivolumab prevents Fab arm exchange with endogenous IgG4 antibodies while retaining the low affinity for activating Fc receptors associated with wild-type IgG4 antibodies. See, e.g., Wang et al. (2014). In yet other embodiments, the antibody comprises a light chain constant region that is a human kappa or lambda constant region. In other embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is a mAb or antigen-binding portion thereof.

[0080] Anti-PD-1 and anti-PD-L1 target the same signaling pathway and have been shown to show similar levels of efficacy in various cancers, including RCC, in clinical trials.See, for example, Brahmer et al. (2012) N Engl J Med 366:2455-65; Topalian et al. (2012a) N Engl J Med 366:2443-54; WO 2013 / 173223. Thus, anti-PD-L1 antibodies can be used in place of anti-PD-1 antibodies in any of the therapeutic methods described herein. In certain embodiments, the anti-PD-L1 antibody is BMS-936559 (previously 12A4 or MDX-1105) (see, for example, U.S. Patent No. 7,943,743; WO 2013 / 173223). In other embodiments, the anti-PD-L1 antibody is MPDL3280A (also known as RG7446). See, e.g., Herbst et al. (2013) J Clin Oncol 31(suppl):3000 and Abstract; U.S. Patent No. 8,217,149. In other embodiments, the anti-PD-L1 antibody is MEDI4736. See, e.g., Khleif (2013) In: Proceedings from the European Cancer Congress 2013; Sep. 27-Oct. 1, 2013; Amsterdam, The Netherlands. Abstract 802). In some embodiments, the immune checkpoint inhibitor, e.g., anti-PD-1 antagonist, used in the present invention is a PD-1Fc fusion protein.

[0081] The preferred immune checkpoint inhibitor suitable for use according to the present invention also includes anti-CTLA-4 antibody.Anti-CTLA-4 antibody can bind to human CTLA-4 and block the interaction between CTLA-4 and human B7 receptor.Since the interaction between CTLA-4 and B7 transmits a signal that leads to the inactivation of T cells that have CTLA-4 receptor, blocking the interaction can effectively induce, enhance or prolong the activation of such T cells, thereby inducing, enhance or prolong immune response.

[0082] HuMAbs that specifically bind CTLA-4 with high affinity are described in U.S. Patent Nos. 6,984,720 and 7,605,238. Other CTLA-4 mAbs are described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121. The CTLA-4 HuMAbs described in U.S. Patent Nos. 6,984,720 and 7,605,238 have been shown to exhibit one or more of the following characteristics: (a) a cytoplasmic affinity of at least about 10 as determined by Biacore analysis; 7 M -1 , or about 10 9 M -1 , or about 10 10 M -1 From 10 11 M -1 Equilibrium binding constant (K α (b) specific binding to human CTLA-4 with a binding affinity reflected by at least about 10 3 , about 10 4 , or about 10 5 m -1 s -1 The kinetic binding constant (k a );(c) at least about 10 3 , about 10 4 , or about 10 5 m -1 s -1 The kinetic dissociation constant (k d); and (d) inhibiting the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Preferred anti-CTLA-4 antibodies for use in the present invention include mAbs that specifically bind human CTLA-4 and exhibit at least one, at least two, or in one embodiment at least three of the above characteristics. In one embodiment, the anti-CTLA-4 antibody is ipilimumab. Ipilimumab is a cost-effective anti-CTLA-4 antibody for the methods described herein. Ipilimumab is a fully human IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, stimulating T cell activation and preferably improving overall survival (OS) in cancer (e.g., advanced melanoma) patients. Another anti-CTLA-4 antibody useful in the methods of the present invention is tremelimumab (also known as CP-675,206). Tremelimumab is a human IgG2 monoclonal anti-CTLA-4 antibody. Tremelimumab is described, for example, in WO 2012 / 122444, U.S. Patent Application Publication No. 2012 / 263677, and WO 2007 / 113648 A2.

[0083] Anti-CTLA-4 antibodies that can be used in the described methods of the invention also include isolated antibodies that specifically bind human CTLA-4 and cross-compete with ipilimumab or tremelimumab for binding to human CTLA-4 or bind to the same epitope region of human CTLA-4 as ipilimumab or tremelimumab. In certain embodiments, the antibodies that cross-compete with ipilimumab or tremelimumab for binding to human CTLA-4 or bind to the same epitope region of human CTLA-4 as ipilimumab or tremelimumab are antibodies that comprise a heavy chain of the human IgG1 isotype. For administration to human subjects, these cross-competing antibodies are chimeric, or humanized or human antibodies. Anti-CTLA-4 antibodies that can be used also include antigen-binding portions of the above antibodies, such as Fab, F(ab")2, Fd, or Fv fragments.

[0084] Lymphocyte activation gene-3 (LAG-3) inhibitors may also be suitable for use according to the present invention. LAG-3 includes human LAG-3 (hLAG-3), variants, isoforms and species homologues of hLAG-3, and analogs that share at least one common epitope with hLAG-3. The term "human LAG-3" refers to human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 with Genbank Accession No. NP 002277. The term "mouse LAG-3" refers to mouse sequence LAG-3, such as the complete amino acid sequence of mouse LAG-3 with Genbank Accession No. NP_032505. LAG-3 is also known in the art as, for example, CD223. The human LAG-3 sequence may differ from the human LAG-3 of Genbank Accession No. NP_002277, for example, by having a conserved mutation or a mutation in a non-conserved region, and the LAG-3 has substantially the same biological function as the human LAG-3 of Genbank Accession No. NP_002277. For example, the biological function of human LAG-3 is to have an epitope in the extracellular domain of LAG-3 that is specifically bound by the antibody of the present disclosure, or the biological function of human LAG-3 is to bind to an MHC class II molecule. Antibodies that bind to LAG-3 are described, for example, in International Publication No. WO 2015 / 042246 and US Patent Application Publication Nos. 2014 / 0093511 and 2011 / 0150892. An exemplary LAG-3 antibody that may be useful in the present invention is 25F7 (described in US Patent Application Publication No. 2011 / 0150892). A further exemplary LAG-3 antibody that may be useful in the present invention is BMS-986016. In one embodiment, an anti-LAG-3 antibody that may be useful in the present invention cross-competes with 25F7 or BMS-986016. In another embodiment, an anti-LAG-3 antibody that may be useful in the present invention binds to the same epitope as 25F7 or BMS-986016. In another embodiment, an anti-LAG-3 antibody comprises the six CDRs of 25F7 or BMS-986016.

[0085] Anti-CD137 targeting agents can be suitable for use according to the present invention.Anti-CD137 antibodies specifically bind to CD137 expressing immune cells, activate the cells, and stimulate immune response against tumor cells, especially cytotoxic T cell response.Antibodies that bind to CD137 are described in US Patent Application Publication No. 2005 / 0095244 and US Patent Nos. 7,288,638, 6,887,673, 7,214,493, 6,303,121, 6,569,997, 6,905,685, 6,355,476, 6,362,325, 6,974,863 and 6,210,669. In some embodiments, the anti-CD137 antibody is urelumab (BMS-663513) described in U.S. Patent No. 7,288,638 (20H4.9-IgG4 [10C7 or BMS-663513]). In some embodiments, the anti-CD137 antibody is BMS-663031 (20H4.9-IgG1) described in U.S. Patent No. 7,288,638. In some embodiments, the anti-CD137 antibody is 4E9 or BMS-554271 described in U.S. Patent No. 6,887,673. In some embodiments, the anti-CD137 antibody is an antibody described in U.S. Patent No. 7,214,493, U.S. Patent No. 6,303,121, U.S. Patent No. 6,569,997, U.S. Patent No. 6,905,685 or U.S. Patent No. 6,355,476. In some embodiments, the anti-CD137 antibody is 1D8 or BMS-469492; 3H3 or BMS-469497; or 3E1 as described in U.S. Patent No. 6,362,325. In some embodiments, the anti-CD137 antibody is an antibody as described in U.S. Patent No. 6,974,863 (e.g., 53A2). In some embodiments, the anti-CD137 antibody is an antibody as described in U.S. Patent No. 6,210,669 (e.g., 1D8, 3B8, or 3E1). In some embodiments, the antibody is Pfizer's PF-05082566 (PF-2566). In other embodiments, the anti-CD137 antibody useful in the present invention cross-competes with the anti-CD137 antibody described herein.In some embodiments, the anti-CD137 antibody binds to the same epitope as an anti-CD137 antibody described herein.

[0086] Agents that target KIR may be suitable for use according to the present invention. The term "Killer Ig-like receptor", "Killer Inhibitory Receptor", or "KIR" refers to a protein or polypeptide encoded by a gene that is a member of the KIR gene family or a cDNA made from said gene. A detailed review of the KIR gene family, including the nomenclature of KIR genes and KIR gene products, and the Genbank accession numbers of exemplary KIRs, is "The KIR Gene Cluster" by M. Carrington and P. Norman, available at the NCBI website under Bookshelf (accessible at ncbi.nlm.nih.gov / books). The term KIR encompasses human KIR (hKIR), variants, isoforms and species homologs of hKIR, and analogs that share at least one common epitope with hKIR. The sequences of human KIR genes and cDNAs, as well as their protein products, are available in public databases, including GenBank. Non-limiting exemplary GenBank entries for human KIRs have the following accession numbers: KIR2DL1: Genbank accession number U24076, NM_014218, AAR16197 or L41267; KIR2DL2: Genbank accession number U24075 or L76669; KIR2DL3: Genbank accession number U24074 or L41268; KIR2DL4: Genbank accession number X97229; KIR2DS1: Genbank accession number X89892; KIR2DS2: Genbank accession number L76667; KIR2DS3: Genbank accession number NMO12312 or L76670 (splice variant); KIR3DL1: Genbank accession number L41269; and KIR2DS4: Genbank accession number AAR26325. KIRs can contain one to three extracellular domains and can have long (i.e., more than 40 amino acids) or short (i.e., less than 40 amino acids) cytoplasmic tails. KIRs are further described in WO 2014 / 055648.Examples of anti-KIR antibodies are described in WO 2014 / 055648, WO 2005 / 003168, WO 2005 / 009465, WO 2006 / 072625, WO 2006 / 072626, WO 2007 / 042573, WO 2008 / 084106, WO 2010 / 065939, WO 2012 / 071411, and WO 2012 / 160448. One anti-KIR antibody that may be useful in the present invention is lirilumab (also referred to as BMS-986015, IPH2102, or the S241P variant of 1-7F9), which is described in WO 2008 / 084106. A further anti-KIR antibody that may be useful in the present invention is 1-7F9 (also referred to as IPH2101), which is described in WO 2006 / 003179.

[0087] Agents that target GITR may be suitable for use according to the present invention. The terms "GITR", "tumor necrosis factor receptor superfamily member 18", "activation-induced TNFR family receptor" and "glucocorticoid-induced TFR-related protein" all refer to proteins that are members of the tumor necrosis factor receptor superfamily. GITR is encoded by the TNFRSF18 gene in humans. It is a 241 amino acid type I transmembrane protein characterized by three cysteine ​​pseudorepeats in the extracellular domain, and specifically protects cells from T cell receptor-induced apoptosis but not from other apoptotic signals, including Fas triggering, dexamethasone treatment, or UV irradiation. See, for example, Nocentini, G, et al. (1997) Proc. Natl. Acad. Sci, USA 94:6216-622). The term GITR encompasses human GITR (hGITR), variants, isoforms and species homologs of hGITR, and analogs that share at least one common epitope with hGITR. Three isoforms of hGITR have been identified, all of which share the same extracellular domain, except for their C-terminal portion. Variant 1 (Accession No. NP_004186) consists of 241 amino acids and represents the longest transcript. It contains an extra coding segment that leads to a frameshift compared to variant 2. The resulting protein (isoform 1) contains a distinct and shorter C-terminus compared to isoform 2. Variant 2 (Accession No. NP683699) encodes the longest protein (isoform 2), consists of 255 amino acids, and is soluble. Variant 3 (Accession No. NP683700) contains an extra coding segment that leads to a frameshift compared to variant 2. The resulting protein (isoform 3) contains a distinct and shorter C-terminus compared to isoform 2 and consists of 234 amino acids. GITR activation increases the proliferation and function of effector T cells, as well as abrogating the suppression induced by activated regulatory T cells. In addition, GITR stimulation promotes anti-tumor immunity by increasing the activity of other immune cells, such as NK cells, antigen-presenting cells and B cells.Examples of anti-GITR antibodies are described in WO 2015 / 031667, WO 2015 / 184,099, WO 2015 / 026,684, WO 2006 / 105021, U.S. Patent Nos. 7,812,135 and 8,388,967, and U.S. Patent Application Publication Nos. 2009 / 0136494, 2014 / 0220002, 2013 / 0183321 and 2014 / 0348841. In one embodiment, an anti-GITR antibody that may be useful in the present invention is TRX518 (e.g., as described in Schaer et a / . Curr Opin Immunol. (2012) Apr; 24(2): 217-224, and WO 2006 / 105021). In another embodiment, the anti-GITR antibody that may be useful in the present invention is MK4166 or MK1248, as well as the antibodies described in WO 2011 / 028683 and US 8,709,424, for example, comprising a VH chain comprising SEQ ID NO: 104 and a VL chain comprising SEQ ID NO: 105, where the SEQ ID NO is from WO 2011 / 028683 or US 8,709,424. In a particular embodiment, the anti-GITR antibody is an anti-GITR antibody described in WO 2015 / 031667, for example, comprising VH CDR1-3 comprising SEQ ID NOs: 31, 71 and 63, respectively, and VL CDR1-3 comprising SEQ ID NOs: 5, 14 and 30, respectively, of WO 2015 / 031667. In certain embodiments, the anti-GITR antibody is an anti-GITR antibody described in WO 2015 / 184099, such as antibody Hum23# or Hum231#2, or a CDR thereof, or a derivative thereof (e.g., pabl967, pabl975, or pabl979).In certain embodiments, the anti-GITR antibody is an anti-GITR antibody described in JP2008278814, WO09 / 009116, WO2013 / 039954, US20140072566, US20140072565, US20140065152, or WO2015 / 026684, or is INBRX-110 (INHIBRx), LKZ-145 (Novartis) or MEDI-1873 (Medlmmune). In certain embodiments, the anti-GITR antibody is an anti-GITR antibody described in PCT / US2015 / 033991 (e.g., an antibody comprising the variable region of 28F3, 18E10, or 19D3).

[0088] Although it is not intended to provide an exhaustive list of all cancer immunotherapeutic agents that may be suitable for use according to the present invention, some agents that are on the market or under development are listed below. Examples of PD-1 antibodies that may be suitable for use according to the present invention include, for example, pembrolizumab, nivolumab, AMP-224, MEDI0680, AMP-514 and REGN2810. Examples of PD-L1 antibodies that may be suitable for use according to the present invention include, for example, atezolizumab, MDX-1105, aurvalumab, avelumab. Examples of CTLA-4 antibodies that may be suitable for use according to the present invention include, for example, ipilimumab and tremelimumab. Examples of KIR antibodies that may be suitable for use according to the present invention include, for example, lirilumab and NNC0141-0000-0100. Examples of LAG3 antibodies that may be suitable for use according to the present invention include, for example, BMS-986016, IMP321, and MK-4280. Examples of GITR antibodies that may be suitable for use according to the present invention include, for example, TRX518, MK-4166, and MK-1248. Examples of OX40 antibodies that may be suitable for use according to the present invention include, for example, MEDI6383, MEDI6469, and MOXR0916. Examples of IDO / IDO1 agents that may be suitable for use according to the present invention include, for example, indoximod, INCB024360, F001287, and NGL919. Examples of TGF-β agents that may be suitable for use according to the present invention include, for example, sotaracept, fresolimumab, travedersen, lucanix, LY2157299, and ACE-536. Examples of CD137 antibodies that may be suitable for use according to the present invention include, for example, urelumab and utomirumab. Examples of CD289 / TLT9 agents that may be suitable for use according to the present invention include MGN1703. Examples of MUC-1 / CD227 agents that may be suitable for use according to the present invention include, for example, ONT-10 and ASN-004.An example of a CCF2 agent that may be suitable for use according to the present invention is PF-04136309. Examples of CD27 antibodies that may be suitable for use according to the present invention include, for example, varlilumab and AMG172. An example of a CD40 antibody that may be suitable for use according to the present invention is dacetuzumab. An example of a SLAMF7 / CS1 antibody that may be suitable for use according to the present invention is elotuzumab. An example of a CD20 agent that may be suitable for use according to the present invention is DI-Leu16-IL2. An example of a CD70 agent that may be suitable for use according to the present invention is ARGX-110. Examples of IL-10 agents that may be suitable for use according to the present invention include, for example, AM0010 and MK-1966. An example of a PSA agent that may be suitable for use according to the present invention is prostvac. An example of a GP100 antibody that may be suitable for use according to the present invention is MDX-1379. An example of a STAT3 agent that may be suitable for use according to the present invention is AZD9150. An example of an IL-12 agent that may be suitable for use according to the present invention includes, for example, veledimex, INXN-2001, MSB0010360N, immunopulse, Gen-1, and INO-9012. An example of an IL-2 agent that may be suitable for use according to the present invention includes, for example, MSB0010445 and RG7813 / RO6895882. An example of an IL-33 agent that may be suitable for use according to the present invention is alarmin IL-33. An example of an M-CSF agent that may be suitable for use according to the present invention is PD-0360324. An example of an hTERT agent that may be suitable for use according to the present invention is INO-1400. An example of an SMAC mimetic agent that may be suitable for use according to the present invention is birinapant. An example of an ImmTACs agent that may be suitable for use in accordance with the present invention is IMCgp100. An example of a CD-40 agent that may be suitable for use in accordance with the present invention is RO7009789. An example of a CD39 agent that may be suitable for use in accordance with the present invention is IPH52.An example of a CEACAM1 agent that may be suitable for use in accordance with the present invention is MK-6018.

[0089] Agents that target VEGF may be suitable for use according to the present invention. Vascular endothelial growth factor ("VEGF") is an endothelial cell-specific mitogen and angiogenesis promoter. VEGF plays an important role in angiogenesis and tumor growth and development. In certain embodiments, the anti-VEGF antagonist is an anti-VEGF antibody, an antigen-binding molecule, or a fragment thereof. In certain embodiments, the anti-VEGF antibody is bevacizumab (described in U.S. Patent No. 7,169,901) or other VEGF antibodies known in the art, including ranibizumab (U.S. Patent No. 7,297,334), VGX-100 (U.S. Patent No. 7,423,125), r84 (U.S. Patent No. 8,034,905), aflibercept (U.S. Patent No. 5,952,199), IMC-18F1 (U.S. Patent No. 7,972,596), IMC-1C11 (PCT / US2000 / 02180), and ramucirumab (U.S. Patent No. 7,498,414).

[0090] Agents that target ALK may be suitable for use in accordance with the present invention. ALK inhibitors act against tumors with anaplastic lymphoma kinase (ALK) perturbations, such as EML4-ALK translocations. ALK inhibitors that may be useful in accordance with the present invention include crizotinib (Pfizer; Xalkori), which has the structure set out in WHO Drug Information, Vol. 28, No. 1, page 79 (2014). TM ), PF-02341066; ceritinib (Novartis), having the structure described in WHO Drug Information, Vol. 28, No. 1, page 79 (2014); Zykadia TM), LDK378); and alectinib (Roche / Chugai; Alecensa, having the structure set forth in WHO Drug Information, Vol. 27, No. 3, page 70 (2013). TM ), RO542802, CH542802). Further examples of ALK inhibitors include, for example, PF-06463922 (Pfizer), NVP-TAE684 (Novartis), AP26113 (Ariad), TSR-011 (Tesaro), X-396 (Xcovery), CEP-37440 (Cephalon / Teva) and RXDX-101 (Igynta; NMS-E628, Nerviano). See, for example, Wang et al., Med. Chem. Commun. 2014, 5:1266. Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK) and its oncogenic variants (i.e., ALK fusion events and selective oncogenic ALK mutations), as well as hepatocyte growth factor receptor (HGFR, c-Met), c-ros oncogene 1 (ROS1) and its oncogenic variants, Recepteur d'Origine Nantais (RON) receptor tyrosine kinases (RTKs), LTK, Trk (TrkA, TrkB, TrkC), and / or insulin receptor. TM) (crizotinib) is approved in the United States for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test, and in Europe, Japan and other jurisdictions for the treatment of ALK-positive NSCLC. Crizotinib and its pharmacologic acceptable salts are described in WO 2006 / 021884, WO 2006 / 021881 and WO 2007 / 066185, and U.S. Patent Nos. 7,858,643, 8,217,057 and 8,785,632. The use of crizotinib in the treatment of abnormal cell growth, such as cancer mediated by ALK or c-MET / HGFR, is described in WO 2007 / 06617 and U.S. Patent No. 7,825,137. The use of crizotinib in the treatment of ROS-mediated cancers is described in WO 2013 / 017989.

[0091] Other antibodies may be suitable for use according to the present invention. In some embodiments, it is an anti-TGFp antibody as described in WO 2009 / 073533. In some embodiments, the antibody is an anti-IL-10 antibody as described in WO 2009 / 073533. In some other embodiments, the antibody is an anti-B7-H4 antibody as described in WO 2009 / 073533. In certain embodiments, the antibody is an anti-Fas ligand antibody as described in WO 2009 / 073533. In some embodiments, the antibody is an anti-CXCR4 antibody (e.g., urocuplumab (BMS-936564)) as described in US Patent Application Publication No. 2014 / 0322208. In some embodiments, the antibody is an anti-mesothelin antibody as described in US Patent Application Publication No. 8,399,623. In some embodiments, the antibody is an anti-HER2 antibody, such as Herceptin (US Pat. No. 5,821,337), trastuzumab, or ado-trastuzumab emtansine (Kadcyla, e.g., WO 2001 / 000244). In some embodiments, the antibody is an anti-CD27 antibody. In some embodiments, the anti-CD27 antibody is varlilumab (also known as "CDX-1127" and "1F5"), a human IgG1 antibody that is an agonist for human CD27, as described, for example, in US Pat. No. 9,169,325. In some embodiments, the antibody is an anti-CD73 antibody. In certain embodiments, the anti-CD73 antibody is CD73.4.IgG2C219S.IgG1.

[0092] In addition to the antibodies described above, other immunotherapeutic anti-cancer agents suitable for use in accordance with the present invention include those that function from a modality including peptides, proteins, small molecules, adjuvants, cytokines, oncolytic viruses, vaccines, bispecific molecules and cellular therapeutics.

[0093] Additional tumor therapies and agents may be used in accordance with the present invention, including, for example, surgery, radiation therapy, treatment with other drugs, antibodies and chemotherapy.

[0094] In some embodiments, the immunotherapeutic agent is administered in conjunction with chemotherapy known in the art. In certain embodiments, the chemotherapy is a platinum-based chemotherapy. The platinum-based chemotherapy agent is a platinum coordination complex. In some embodiments, the platinum-based chemotherapy is a platinum doublet chemotherapy. In one embodiment, the chemotherapy is administered at a dose approved for a particular indication. In some embodiments, the platinum-based chemotherapy is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or a combination thereof. In certain embodiments, the platinum-based chemotherapy is other platinum-based chemotherapy known in the art. In some embodiments, the chemotherapy is the nucleotide analog gemcitabine. In an embodiment, the chemotherapy is an antifolate. In an embodiment, the antifolate is pemetrexed. In certain embodiments, the chemotherapy is a taxane. In other embodiments, the taxane is paclitaxel. In other embodiments, the chemotherapy is a nucleoside analog. In one embodiment, the nucleoside analog is gemcitabine. In some embodiments, the chemotherapy is any other chemotherapy known in the art.

[0095] In certain embodiments, the immunotherapeutic agent is administered in combination with a tyrosine kinase inhibitor. In certain embodiments, the tyrosine kinase inhibitor is gefitinib, erlotinib, a combination thereof, or other tyrosine kinase inhibitors known in the art. In some embodiments, the tyrosine kinase inhibitor acts on epidermal growth factor receptor (EGFR). In certain embodiments, the immunotherapeutic agent is administered in combination with a Bruton's tyrosine kinase (Btk) inhibitor. Btk inhibitors useful for treating cancer include those taught in U.S. Patent No. 8,940,725 (Yamamoto et al.) and U.S. Patent No. 7,514,444 (Honigberg et al.), U.S. Patent Application Publication No. 2015 / 0118222 (Levy et al.) and WO 2017 / 059224.

[0096] Standard treatment therapies for various types of cancer are well known to those skilled in the art. For example, the National Comprehensive Cancer Network (NCCN), an alliance of 21 major cancer centers in the United States, provides the NCCN Clinical Practice Guidelines in Oncology (NCCN GUIDELINES), which provide detailed, up-to-date information on standard treatment therapies for a wide variety of cancers. TM ) (see NCCN GUIDELINES, 2014).

[0097] As an example of tumor treatment, a therapeutically effective amount of an immunotherapeutic agent can inhibit cell proliferation or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%, compared to untreated subjects, and in certain embodiments, compared to patients treated with standard treatment therapy. In other embodiments of the present invention, tumor regression can be observed and continued for at least about 20 days, at least about 40 days, or at least about 60 days. Despite these ultimate measures of therapeutic efficacy, the evaluation of an immunotherapeutic agent must also take into account "immune-related" response patterns.

[0098] The present invention provides a method of cancer treatment using one or more immunotherapeutic anti-cancer agents, such as anti-PD-1 antibodies, as monotherapy or in combination with other anti-cancer agents and glutamate modulating agents. In one embodiment, the cancer is a solid tumor. In another embodiment, the cancer is a primary cancer. In another embodiment, the cancer is a metastatic or recurrent cancer. In some embodiments, the subject is a human patient. In certain embodiments, the subject is a chemotherapy-naive patient (e.g., a patient who has not previously undergone any chemotherapy). In other embodiments, the subject has undergone another cancer treatment (e.g., chemotherapy) but is resistant or unresponsive to such another cancer treatment.

[0099] The dosing regimen is adjusted to provide the optimal desired response, for example, the maximum therapeutic response and / or the minimum adverse effects.In certain embodiments, the method of the present invention can be used with flat dose or weight-based dose.In further embodiments, the immunotherapeutic agent is administered as a flat dose.In further embodiments, the immunotherapeutic agent is administered as a weight-based dose. For administration of an anti-PD-1 antibody as a monotherapy or in combination with another anti-cancer agent, the dosage may be in the range of about 0.01 to about 20 mg / kg, about 0.1 to about 10 mg / kg, about 0.1 to about 5 mg / kg, about 1 to about 5 mg / kg, about 2 to about 5 mg / kg, about 7.5 to about 12.5 mg / kg, or about 0.1 to about 30 mg / kg of the subject's body weight, or in the range of about 80 mg to at least 800 mg, about 80 mg to about 700 mg, about 80 mg to about 600 mg, about 80 mg to about 500 mg, about 80 mg to about 400 mg, about 80 mg to about 300 mg, about 100 mg to about 300 mg, or about 200 mg to about 300 mg. For example, the dose can be about 0.1, about 0.3, about 1, about 2, about 3, about 5, or about 10 mg / kg body weight, or about 0.3, about 1, about 2, about 3, or about 5 mg / kg body weight; or about 80 mg, about 100 mg, about 160 mg, about 200 mg, about 240 mg, about 300 mg, about 320 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg. The administration schedule is typically designed to achieve an exposure that results in sustained receptor occupancy (RO) based on the typical pharmacokinetic properties of the antibody. Exemplary treatment regimens involve administration about once per week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once per month, about once every 3-6 months or more. In certain embodiments, the anti-PD-1 antibody, such as nivolumab, is administered to the subject about once every two weeks. In other embodiments, the antibody is administered about once every three weeks. The dose and schedule can be changed during the course of treatment.For example, a dosing schedule for anti-PD-1 monotherapy can include the following administration of Ab: (i) about every 2 weeks for about a 6 week cycle; (ii) about 6 doses about every 4 weeks, then about every 3 months; (iii) about every 3 weeks; (iv) about 3 to about 10 mg / kg, then about 1 mg / kg every 2 to 3 weeks. Considering that the half-life of IgG4 antibodies is typically 2 to 3 weeks, dosing regimens for the anti-PD-1 antibodies of the invention include at least about 0.3 to at least about 10 mg / kg body weight, at least about 1 to at least about 5 mg / kg body weight, or at least about 1 to at least about 3 mg / kg body weight, or at least about 80 to at least about 800 mg, by intravenous administration, with the antibody administered about every 14 to 21 days, in cycles of up to about 6 or about 12 weeks, until complete remission or until progressive disease is confirmed. In certain embodiments, anti-PD-1 monotherapy is administered at 3 mg / kg every 2 weeks until progressive disease, or for several weeks until progressive disease or unacceptable toxicity. In some embodiments, antibody treatment, or combination treatment described herein, is continued for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years. Other examples of doses for immunotherapy anticancer agents can be about 1-100 mg / kg; for example, 1 mg / kg, 2 mg, kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 20 mg / kg, 25 mg / kg, 50 mg / kg, 75 mg / kg, 100 mg / kg, or intermediate values.

[0100] When used in combination with other anticancer drugs, the dose of the immunotherapeutic agent may be less than the monotherapy dose. For example, a dose of nivolumab that is typically less than 3 mg / kg but not less than 0.001 mg / kg is a subtherapeutic dose. A subtherapeutic dose of an anti-PD-1 antibody used in the methods described herein is greater than 0.001 mg / kg and less than 3 mg / kg. In some embodiments, the subtherapeutic dose is about 0.001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 1 mg / kg, or about 0.001 mg / kg to about 0.1 mg / kg body weight. In some embodiments, the subtherapeutic dose is at least about 0.001 mg / kg, at least about 0.005 mg / kg, at least about 0.01 mg / kg, at least about 0.05 mg / kg, at least about 0.1 mg / kg, at least about 0.5 mg / kg, or at least about 1.0 mg / kg body weight. In some embodiments, the subtherapeutic flat dose is less than about 240 mg every two weeks, for example, about 160 mg or about 80 mg every two weeks. Receptor occupancy data for 15 subjects administered nivolumab 0.3 mg / kg to 10 mg / kg shows that in this dose range, PD-1 occupancy appears to be dose-independent. Across all doses, the mean occupancy was 85% (range, 70% to 97%), with a mean plateau occupancy of 72% (range, 59% to 81%) (Brahmer et al. (2010) J Clin Oncol 28:3167-75). In some embodiments, a dosage of 0.3 mg / kg may allow sufficient exposure to result in maximal biological activity.

[0101] In certain embodiments, the dose of the immunotherapeutic agent is a fixed dose in the pharmaceutical composition. In other embodiments, the method of the present invention can be used with a flat dose (a dose administered to a patient regardless of the patient's weight). For example, the flat dose of nivolumab can be about 240 mg. For example, the flat dose of pembrolizumab can be about 200 mg. In some embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose of about 240 mg. In some embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose of about 360 mg. In an embodiment, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose of about 480 mg. In one embodiment, 360 mg of the anti-PD-1 antibody or antigen-binding fragment is administered once every three weeks. In another embodiment, 480 mg of the anti-PD-1 antibody or antigen-binding fragment is administered once every four weeks.

[0102] Ipilimumab (Yervoy TM )) is approved for the treatment of melanoma at 3 mg / kg intravenously, once every 3 weeks for 4 doses. In certain embodiments, the dose of anti-CTLA-4 antibody is a flat dose administered to patients regardless of body weight. In certain embodiments, the flat dose of anti-CTLA-4 antibody is about 80 mg.

[0103] Thus, in some embodiments, about 3 mg / kg is the reconsideration dose of ipilimumab in combination with an anti-PD-1 antibody, but in certain embodiments, an anti-CTLA-4 antibody such as ipilimumab, when combined with an anti-PD-1 antibody, such as nivolumab, may be administered in the range of about 0.3 to about 10 mg / kg, about 0.5 to about 10 mg / kg, about 0.5 to about 5 mg / kg, or about 1 to about 5 mg / kg body weight about every 2 or 3 weeks. In other embodiments, ipilimumab is administered on a different dosing schedule than the anti-PD-1 antibody. In some embodiments, ipilimumab is administered about every week, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, or about every 15 weeks.

[0104] A dose of ipilimumab that is typically less than 3 mg / kg but not less than 0.001 mg / kg every 3 weeks is a subtherapeutic dose. A subtherapeutic dose of an anti-CTLA-4 antibody used in the methods herein is greater than 0.001 mg / kg and less than 3 mg / kg. In some embodiments, a subtherapeutic dose is about 0.001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 1 mg / kg, or about 0.001 mg / kg to about 0.1 mg / kg body weight. In some embodiments, a subtherapeutic dose is at least about 0.001 mg / kg, at least about 0.005 mg / kg, at least about 0.01 mg / kg, at least about 0.05 mg / kg, at least about 0.1 mg / kg, at least about 0.5 mg / kg, or at least about 1.0 mg / kg body weight. In certain embodiments, the combination of anti-PD-1 antibody or anti-PD-L1 antibody and anti-CTLA-4 antibody is administered intravenously to the subject about every 2 or 3 weeks for 1, 2, 3 or 4 times during the induction phase. In certain embodiments, the combination of anti-PD-1 antibody and anti-PD-L1 antibody is administered intravenously about every 2 weeks or about every 3 weeks for about 4 times during the induction phase. The induction phase is followed by a maintenance phase in which the subject is administered only anti-PD-1 antibody or anti-PD-L1 antibody at a dose of about 0.1, about 0.3, about 1, about 2, about 3, about 5 or about 10 mg / kg, or about 40 mg, about 80 mg, about 100 mg, about 160 mg, about 200 mg, about 240 mg, about 320 mg or about 400 mg, about every 2 or 3 weeks, as long as efficacy of treatment is demonstrated or until unmanageable toxicity or disease progression occurs. In certain embodiments, nivolumab is administered at a dose of about 3 mg / kg body weight or about 240 mg about every two weeks during the maintenance phase.

[0105] In certain embodiments, the dose of the anti-PD-1 antibody or anti-PD-L1 antibody is a fixed dose in a pharmaceutical composition with a second anti-cancer agent.In certain embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the anti-CTLA-4 antibody are formulated as a single composition in which the dose of the anti-PD-1 antibody or anti-PD-L1 antibody and the dose of the anti-CTLA-4 antibody are combined in a ratio of 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:3, 1:1, 3:1, 5:1, 10:1, 20:1, 30:1, 40:1, or 50:1.

[0106] For the combination of immunotherapeutic agents and other anticancer agents, these agents are typically administered at their approved doses.Treatment continues as long as clinical benefit is observed or until unacceptable toxicity or disease progression occurs.Nevertheless, in certain embodiments, the dose of these anticancer agents administered is significantly lower than the approved dose, i.e., the subtherapeutic dose of the agent is administered in conjunction with immunotherapeutic agents.

[0107] In certain embodiments, the immunotherapy anticancer agent is administered in conjunction with the standard treatment of certain types of cancer.In further embodiments, the immunotherapy anticancer agent is administered in conjunction with chemotherapy, including 5-FU, etoposide and platinum-based drugs (e.g., carboplatin or cisplatin).In some embodiments, the immunotherapy anticancer agent is administered before, at the same time, or after radiation therapy.In some embodiments, the immunotherapy anticancer agent is administered before, at the same time, or after surgical resection.

[0108] The dose and frequency vary depending on the half-life of the immunotherapeutic anticancer agent in the subject. Generally, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies and non-human antibodies. The dose and frequency can vary depending on whether the treatment is preventive or therapeutic. In preventive applications, relatively low doses are typically administered over a long period of time at relatively infrequent intervals. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, relatively high doses at relatively short intervals are often required until the progression of the disease slows or stops, or the patient shows partial or complete remission of the symptoms of the disease. The patient can then be administered a preventive regimen.

[0109] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being excessively toxic to the patient. The selected dosage level depends on various pharmacokinetic factors, including the activity of the particular composition of the present invention used, the route of administration, the time of administration, the excretion rate of the particular compound used, the duration of treatment, other drugs, compounds and / or substances used in combination with the particular composition used, the age, sex, weight, condition, overall health and previous medical history of the patient being treated, and similar factors well known in the medical field. The composition of the present invention, including an immunotherapeutic agent, can be administered by one or more routes of administration using one or more of a variety of methods well known in the art. As will be apparent to one skilled in the art, the route and / or mode of administration will vary depending on the desired result.

[0110] The immunotherapeutic agent of the present invention can be constituted in a composition, for example, a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. In one embodiment, the carrier for the composition containing an antibody is one suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion), while the carrier for the composition containing a peptide, protein, small molecule, adjuvant, cytokine, oncolytic virus, vaccine, bispecific molecule and cellular therapeutic agent is one suitable for non-parenteral administration, for example, oral administration. The pharmaceutical composition of the present invention can include one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and / or adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents.

[0111] Suitable glutamate modulators for use according to the present invention include (a) agents that promote the regulation, control, attenuation or enhancement of (i) ionotropic glutamate receptors; (ii) metabotropic glutamate receptors; or (iii) glutamate transporters; (b) agents that inhibit glutamate release; or (c) agents that regulate, control, attenuation or enhancement of glutamate or glutamine metabolism. Ionotropic glutamate receptors include NMDA, AMPA and kainate. Metabotropic glutamate receptors include type 1 receptors, including mGluR1 and mGluR5; type II receptors, including mGluR2 and mGluR3; and type III receptors, including mGluR4, mGluR6, mGluR7 and mGluR8. Glutamate transporters can be expressed in glia or neurons. Preferably, the glutamate modulating agent (i) normalizes glutamate levels in the patient; (ii) attenuates or normalizes glutamate release in the patient; or (iii) normalizes, enhances or increases glutamate uptake in the patient. The glutamate modulating agent can cause a decrease in glutamine / glutamate levels or increase glutamate circulation by increasing the expression of excitatory amino acid transporters, thereby reducing the decrease in proliferation and effector function.

[0112] Preferred glutamate modulating agents are selected from riluzole, memantine, n-acetylcysteine, amantadine, topiramate, pregabalin, lamotrigine, ketamine, s-ketamine, AZD8108, AZD6765 (lanicemine), BHV-4157 (trigriluzole), dextromethorphan, AV-101, CERC-301 and GLY-13, and pharma- ceutically acceptable salts, prodrugs or analogs thereof. Riluzole, currently commercially available as RILUTEK® (riluzole), available from Sanofi-Aventis (Bridgewater, NJ), has the structure shown below. [ka]

[0113] The term "riluzole" also refers to all prodrugs, enantiomers or derivatives, and pharma- ceutically acceptable salts thereof, unless otherwise noted. The term "riluzole prodrug" refers to a compound that is a derivative from riluzole with modifications. Riluzole prodrugs can also refer to compounds that are metabolized by the body to the active form of riluzole.

[0114] Certain preferred riluzole prodrugs have the structure: [ka] [In the formula, R 23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2. Those skilled in the art will recognize that similar or variant prodrugs can be prepared from other glutamate modulating agents. Such agents may be useful as part of the combinations of the present invention.

[0115] One particularly preferred glutamate modulating agent, trigriluzole, has the following formula: [ka] has.

[0116] Prodrugs of riluzole are described, for example, in U.S. Patent Application No. 14 / 385,551, U.S. Patent Application No. 14 / 410,647, PCT Application No. PCT / US2016 / 019773 and PCT Application No. PCT / US2016 / 019787. Sublingual formulations of riluzole that provide stability and superior properties are described in PCT Application No. PCT / US2015 / 061106 and PCT Application No. PCT / US2015 / 061114.

[0117] Glutamate modulators can exist as isotopically labeled forms of the compounds detailed herein.Isotopically labeled compounds have the structure represented by the formulas described herein, except that one or more atoms are replaced with atoms having selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g. 2 H (deuterium, D), 3 H (tritium), n C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 These include, but are not limited to, S, CI and I. Various isotopically labeled compounds of the present disclosure, such as 3 H, 13 C and 14 Also provided are those incorporating a radioisotope such as C. Such isotopically labeled compounds may be useful for metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substance tissue distribution assays, or for radiation treatment of subjects (e.g., humans). In some cases, pharma- ceutically acceptable salts or hydrates of the isotopically labeled compounds described herein are also provided.

[0118] In some variations, the compounds described herein may be altered such that one to "n" hydrogens bonded to a carbon atom are replaced with deuterium, where "n" is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus are useful for increasing the half-life of the compound when administered to a subject. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0119] Deuterium labeled or substituted therapeutic compounds of the present disclosure may have improved drug metabolism and pharmacokinetic (DMPK) properties with respect to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can confer certain therapeutic advantages caused by greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements and / or improved therapeutic index. 18 F-labeled compounds can be useful for PET or SPECT studies.The isotopically labeled compounds of the present disclosure can generally be prepared by carrying out procedures known to those skilled in the art by using readily available isotopically labeled reagents instead of nonisotopically labeled reagents.Deuterium in this context is considered as a substituent in the compounds described herein.

[0120] The concentration of such heavy isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, an atom that is not specifically designated as a particular isotope is meant to include the stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition.

[0121] The glutamate modulating agent of the present invention can be administered orally, sublingually, intranasally, bucally, subcutaneously, or by other suitable delivery means. The glutamate modulating agent can be a prodrug, sustained release vehicle, delayed release vehicle, or other suitable delivery form that releases the agent in the body. The glutamate modulating agent and the immunotherapeutic agent can be delivered simultaneously or sequentially. When the agents are delivered sequentially, either agent can be administered first, and the separation of time can include that the administration of one agent is completely completed before the administration of the other agent begins, or they can be mixed in time. Typically, the glutamate modulating agent is administered closest to the administration of the immunotherapeutic anticancer agent, for example, within one week, one hour, one minute before or after the administration of the immunotherapeutic anticancer agent, or simultaneously with the immunotherapeutic anticancer agent.

[0122] The dosage of the glutamate modulating agent for use with the immunotherapeutic agent administered may depend on the subject being treated, including the age, sex, weight and general health of the subject being treated.In this regard, the exact amount of the agent to be administered depends on the judgment of the physician.When determining the effective amount of the glutamate modulating agent and the immunotherapeutic agent administered in treating or alleviating the condition related to the condition and disorder, the physician may evaluate clinical factors, including the severity of the condition or the progression of the disorder.In some conditions, rapid absorption of the glutamate modulating agent or the immunotherapeutic agent may be desired.The effective amount of the treatment varies depending on the subject and the condition being treated, the severity of the pain, and the method of administration, and can be routinely determined by those skilled in the art.

[0123] A glutamate modulating agent as part of a formulation for treating a cancer or condition may be administered at about 400 mg / day or less, about 300 mg / day or less, about 150 mg / day or less, about 100 mg / day or less, about 70 mg / day or less, about 60 mg / day or less, about 50 mg / day or less, about 42.5 mg / day or less, about 37.5 mg / day or less, about 35 mg / day or less, about 20 mg / day or less, about 17.5 mg / day or less, about 15 mg / day or less, about 10 mg / day or less, about 5 mg / day or less, or about 1 mg / day or less.

[0124] The pharmaceutical compositions of the present invention comprising glutamate modulators typically also contain other pharma- ceutically acceptable carriers and / or excipients, such as binders, lubricants, diluents, coating agents, disintegrants, barrier layer components, glidants, colorants, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizers, suspending agents, and mixtures thereof. Those skilled in the art will know what other pharma-ceutically acceptable carriers and / or excipients may be included in the formulations of the present invention. The choice of excipients depends on the characteristics of the composition and the nature of other pharma-ceutically active compounds in the formulation. Suitable excipients are known to those skilled in the art (see Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., McGraw Hill) and are used to obtain novel sublingual formulations with unexpected properties.

[0125] Examples of pharma- ceutically acceptable carriers that can be used to prepare the pharmaceutical compositions of the present invention include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, polyvinyl-pyrrolidone (PVP), talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, pyrogen-free water, and combinations thereof.If desired, disintegrants can be added as well, and exemplary disintegrants include, but are not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.The compositions can be prepared by any of the methods of pharmacy, but all methods include the step of combining one or more of the above chemical agents with a carrier that constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention can be prepared by conventional methods known in the art, such as by conventional mixing, dissolving, granulating, sugar-coating, levigating, emulsifying, encapsulating, encapsulating, lyophilizing processes, etc. Glutamate modulators, such as riluzole and its pharmaceutically acceptable salts, can be formulated into dosages suitable for sublingual, nasal or buccal administration using pharmaceutically acceptable carriers well known in the art. Such carriers allow the glutamate modulators to be formulated into dosage forms such as tablets, powders, pills, capsules, liquids, gels, films, syrups, slurries, suspensions, etc.

[0126] Some glutamate modulators can be administered sublingually. PCT Application No. PCT / US2015 / 061106 and PCT Application No. PCT / US2015 / 061114 describe sublingual formulations of the preferred glutamate modulator, riluzole. The sublingual formulation can be administered in an effective amount to a subject in need. The subject can be an animal or a human. When the glutamate modulator is prepared as a sublingual formulation, the sublingually administered chemical agent or drug can diffuse through the mucous membrane under the tongue into the capillaries and then enter the venous circulation of the subject. Thus, sublingual administration can be advantageous over oral administration in that it allows direct or more rapid entry into the venous circulation without the risk of degradation in the digestive tract, alteration due to drug metabolism in the liver, etc.

[0127] The sublingual formulation useful in the present invention comprises an effective amount of riluzole or a pharma- ceutically acceptable salt, solvate, anomer, enantiomer, hydrate or prodrug thereof. The formulation provides sufficient solubility for riluzole to be incorporated into the sublingual formulation and delivered sublingually in relatively large amounts. The formulation is preferably a modified orally disintegrating formulation of riluzole. Excipients including mannitol and gelatin are mixed, solubilized with water, and degassed before mixing with riluzole, an active pharmaceutical ingredient (or "API"), which has been milled separately. The particle size (D50) of the API is less than about 2 microns. The mixture is freeze-dried by flash freezing and then lyophilized. The formulation has good oral palatability. The effective amount of glutamate modulating agent for the sublingual formulation useful in the present invention to achieve a lower therapeutic dose may be less than that of the orally administered drug. Furthermore, the effective dose of the sublingual formulation of glutamate modulating agent may be about 1-95% of the orally administered drug. To the extent a sublingual formulation of an immunotherapeutic agent can be prepared, it may also have improved properties.

[0128] In one embodiment of the present invention, the glutamate modulating agent is provided in a sublingual formulation in the form of an orally soluble or disintegrating tablet (ODT). The ODT used herein is prepared by mixing the glutamate modulating agent and / or immunotherapeutic agent with a water-soluble diluent and compressed into a tablet. A suspension containing the active product can be prepared with suitable excipients, and the suspension can be dispensed into a blister pack and lyophilized. An exemplary lyophilized formulation platform that can be used for the ODT is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, excipients including water are mixed, and the glutamate modulating agent is separately ground to size and mixed with the excipients. The suspension is then lyophilized by quick freezing and lyophilization. Other methods for preparing ODT can be used without limitation, detailed descriptions of which general methods are found in, for example, U.S. Pat. Nos. 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270; 6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978; 6,908,62 Nos. 6, 6,908,626, 6,982,251, 7,282,217, 7,425,341, 7,939,105, 7,993,674, 8,048,449, 8,127,516, 8,158,152, 8,221,480, 8,256,233, and 8,313,768 (each of which is incorporated herein by reference in its entirety). Some glutamate modulating agents can be administered sublingually. PCT Application Nos. PCT / US2015 / 061106 and PCT Application No. PCT / US2015 / 061114 describe sublingual formulations of the preferred glutamate modulating agent, riluzole. The sublingual formulation can be administered in an effective amount to a subject in need thereof. The subject can be an animal or a human.

[0129] The clinical or therapeutic effect of sublingually formulated glutamate modulators may have improved pharmacokinetic profiles for pharmaceutical drugs as measured by standard test parameters.When glutamate modulators are administered sublingually, the Tmax, Cmax and AUC of the drug may be improved compared to the oral administration of the same compound at the same dose.For example, sublingual formulations of glutamate modulators may have a greater Cmax than orally administered glutamate modulators to provide therapeutically beneficial effects.Sublingual formulations of glutamate modulators may have an earlier or smaller Tmax than orally administered glutamate modulators to provide therapeutically beneficial effects, and in some cases a more rapid therapeutic effect.Alternatively, sublingual formulations of glutamate modulators may have a greater AUC per mg of drug than orally administered glutamate modulators.In addition, glutamate modulators may make immunotherapeutic agents more effective, so that less immunotherapeutic agent may be required to achieve the same results while reducing inherent side effects.

[0130] In one embodiment, the present invention provides a method of treating cancer, comprising sublingually administering to a subject in need of the treatment an effective amount of a glutamate modulating agent or its pharma- ceutically acceptable salt and an anti-cancer immunotherapeutic agent or its pharma- ceutically acceptable salt or prodrug. The combination of these two drugs can be administered in a single dose as a combination product, simultaneously using the same or different formats, or sequentially using the same or different delivery forms. For example, if both can be in a tablet or part of a sublingual dosage form, they can be administered together. Similarly, if the immunotherapeutic agent can only be administered by injection (bolus or intravenous) and the glutamate modulating agent can be administered in the same format, it can also be used for simultaneous or sequential administration. However, if the immunotherapeutic agent can only be delivered by injection (e.g., if it is an antibody) and the glutamate modulating agent can be administered as a tablet or sublingually, the delivery of the two agents can occur by different formats. Further details regarding the specific administration method of the immunotherapeutic agent and the glutamate modulating agent can be determined by those skilled in the art.

[0131] Identification of a subject in need of such treatment may be the judgment of the subject or a medical professional, and may be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). The identified subject may be an animal or a human, particularly a human, in need of the treatment. Such treatments are suitably administered to subjects, particularly humans, who are suffering from a disease.

[0132] The therapeutic effect of the combination product, particularly when applied to the treatment of symptoms, may be evident within about a few minutes to about an hour after its administration. In particular, the therapeutic effect may begin within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 20 minutes, about 60 minutes, about 90 minutes after administration. However, long-term cure or remission of the disease may not occur for weeks or months after administration.

[0133] The effect on the symptoms may be maintained for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 2 days, or about 3 days or more after administration. Hopefully, a long-term effect on the condition is achieved, eliminating the disease and symptoms permanently.

[0134] Typical administration frequencies for glutamate modulating agents include once a day, twice a day, three times a day, four times a day, once every other day, once a week, twice a week, three times a week, four times a week, once every two weeks, once or twice a month, etc.

[0135] In certain embodiments, the immunotherapy of the invention in combination with a glutamate modulating agent (e.g., administration of an anti-PD-1 antibody or anti-PD-L1 antibody, and optionally another anti-cancer agent) effectively increases the survival time of the subject. In some embodiments, the combination therapy of the invention increases the survival time of the subject compared to the standard of care therapy. In certain embodiments, the therapy of the invention increases the overall survival time of the subject. In some embodiments, the subject exhibits an overall survival time of at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration. In some embodiments, the survival time or overall survival of a subject is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or at least about 75% when compared to another subject treated with only standard treatment therapy. In other embodiments, the survival time or overall survival of a subject is increased by at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years when compared to another subject treated with only standard treatment therapy.

[0136] In certain embodiments, the combination therapy of the present invention effectively increases the progression-free survival of the subject.For example, the progression-free survival of the subject increases by at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 1 year, when compared with another subject treated with standard treatment therapy alone.In certain embodiments, after administration of immunotherapy (e.g., anti-PD-1 antibody or anti-PD-L1 antibody therapy) with glutamate modulating agent, the subject shows an overall response rate of at least about 30%, 35%, 36%, 37%, 39%, 40%, 45% or 50%, compared with the response rate after administration of standard treatment therapy.

[0137] In certain embodiments, the combination therapy of the present invention provides an improvement in treatment response, which can be one or more of, for example, overall survival, quality of life, overall response rate, duration of response, progression-free survival, patient-reported outcome, minimal residual disease, or immune response.

[0138] A preferred glutamate regulator is riluzole, and a preferred immunotherapeutic agent is checkpoint inhibitor, such as anti-PD-1 antibody.It is believed that glutamate regulator can make cancer cells more sensitive to anticancer agents, such as immunotherapeutic agents.Also, glutamate regulator can sensitize patients to make immunotherapeutic agent treatment more effective.

[0139] Therapeutic kits comprising an immunotherapeutic agent (e.g., anti-PD-1 antibody or and anti-PD-L1 antibody) and / or a glutamate modulating agent (e.g., riluzole), and optionally another anti-cancer agent, are also within the scope of the present invention. The kit typically includes a label and instructions describing the intended use of the contents of the kit. The term label includes any written or recorded material supplied on or with the kit, or that otherwise accompanies the kit. In certain embodiments, for treating a human patient, the kit comprises an anti-human PD-1 antibody or anti-human PD-L1 antibody described herein, such as nivolumab or pembrolizumab. In other embodiments, the kit comprises an anti-human CTLA-4 antibody described herein, such as ipilimumab or tremelimumab. In other embodiments, the kit comprises a glutamate modulating agent, such as riluzole or trigrilozole.

[0140] Various solid malignant tumors have been shown to overexpress phosphate-dependent glutaminase (GLS), which converts glutamine to glutamate, highlighting the role of glutamine in cancer metabolism. However, glutamate is an important nitrogen "waste" bank and is important in various cellular metabolic pathways. Thus, reduced glutamine / glutamate levels on immune cells may reduce proliferation and effector function, limiting antitumor immune-mediated responses. Although this effect is evident for GLS-producing tumor cells, glutamate receptors are found on numerous other tumor cells, and it is conceivable that this combination therapy may be effective against those cells as well. EXAMPLES

[0141] The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention. In some examples, abbreviations are used that are known to those skilled in the art or that can be easily accessed from documents cited in the examples, such as the Summary of Product Characteristics published by the European Medicines Agency.

[0142] Example 1 In this example, the effect of the combination of the glutamate modulating agent BHV-4157 along with the immunotherapeutic agent anti-PD-1 was compared to either alone in a glioma model essentially as described in Zeng, J., et al., Int J Radiat Oncol Biol Phys., 2013 June 1; 86(2):343-349, portions of which are reproduced below.

[0143] cell GL261-Luc cells are grown in Dulbecco's modified Eagle's medium (DMEM) + 10% fetal bovine serum + 1% penicillin streptomycin at 37°C in a humidified incubator (Gibco) maintained at 5% CO and 5% O2.

[0144] Tumor models Female C57BL / 6J mice (Harlan) aged 4-6 weeks or 6-8 weeks are used for orthotopic glioma experiments as described in Sonabend AM, Velicu S, Ulasov IV, et al. A safety and efficacy study of local delivery of interleukin12 transgene by PPC polymer in a model of experimental glioma. Anticancer Drugs. 2008;19:133-142. To establish syngeneic gliomas, 130,000 GL261-Luc cells are stereotaxically injected into the left striatum over 1 min in a volume of 1 μL at the following coordinates: 1 mm anterior, 1 mm lateral from bregma, and 3 mm deep from the cortical surface. Tumor burden is monitored by luciferase imaging on days 7, 21, and 35 after implantation, and mice are randomly assigned to treatment arms based on tumor radiance such that the mean tumor radiance in each group is approximately equivalent. Animals are euthanized when they show predefined signs of neurological deficit (failure to ambulate, weight loss >20% body weight, lethargy, hunched posture). Tumor incidence is 100%. In survival experiments, each arm has 6-10 mice. All experiments are repeated at least three times.

[0145] Anti-PD-1 antibody The hamster anti-mouse PD-1 monoclonal antibody-producing hybridoma G4 is used to produce the antibody as described in Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65:1089-1096.

[0146] Specific Protocol 130,000 GL261 cells were implanted intracranially into the left striatum of 4-6 week old female C57BL / 6J mice each. Mice were housed and maintained in accordance with Institutional Animal Care and Use Committee protocols at the Johns Hopkins University Animal Facility. Mice were imaged by bioluminescence IVIS® imaging (Perkin Elmer) on days 7, 21, and 35 to assess tumor burden and were randomly assigned into groups of 10 mice per arm as follows: 1. Control 2. Anti-PD-1 3. Triglylusol 15mg / kg 4. Triglylusol 30mg / kg 5. Triglylusol 45mg / kg 6. Anti-PD-1 + triglylusol 15mg / kg 7. Anti-PD-1 + triglylusol 30mg / kg 8. Anti-PD-1 + triglylusol 45mg / kg

[0147] The protocol is shown in the diagram below: [ka]

[0148] Day 0 represents the day of intracranial implantation. Control arm 1 received no treatment. Control arm 2 received αPD-1 alone at a dose of 200 μg / animal by intraperitoneal injection on days 10, 12, and 14. Control arms 3, 4, and 5 received BHV-4157 alone at doses of 15, 30, and 45 mg / kg (respectively) by intraperitoneal injection daily starting on day 10. Control arms 6, 7, and 8 received BHV-4157 at doses of 15, 30, and 45 mg / kg (respectively) by intraperitoneal injection daily starting on day 10 and αPD-1 at a dose of 200 μg / animal by intraperitoneal injection on days 10, 12, and 14.

[0149] Treatment was terminated when mice demonstrated no tumor burden by IVIS imaging. Animals were euthanized according to human endpoints including central nervous system dysfunction, hunched posture, lethargy, weight loss and lameness.

[0150] The purpose of the experiment was to see if the combination therapy would provide benefits over either therapy alone. The results are shown in Figure 1. As is evident from Figure 1, the combination therapy is substantially superior to either individual therapy, and the effects appear to be synergistic, not merely additive. Thus, the effect of the glutamate modulating agent on glutamate / glutamine metabolism appears to weaken tumor cells and make anti-PD-1 antibodies more effective. Quite surprisingly, according to the present invention, the survival rate of mice treated with a glutamate modulating agent in conjunction with an immunotherapy anticancer agent was approximately double that of mice treated with an immunotherapy anticancer agent alone, for survival rates of mice at approximately 30, 40 and 60 days after implantation. Table 1 below shows the data from Example 1.

[0151] [Table 1]

[0152] From Table 1, it can be seen that by day 26, mice in arm 1 (control) had 0% survival rate, mice in arm 2 (PD-1) had 50% survival rate, and mice in arms 6, 7, and 8 had at least 70-80% survival rate. Thus, on day 26, the mouse survival ratio (MSR 26 ) was approximately 1.4-1.6 (i.e., 70 / 50 and 80 / 50). On day 28, mice in arm 1 (control) had 0% survival, mice in arm 2 (PD-1) had 30% survival, and mice in arms 6, 7, and 8 had at least 60-80% survival. Thus, on day 28, the mouse survival ratio (MSR 28) was approximately 2.0-2.6 (i.e., 60 / 30 and 80 / 30). At day 60, mice in arm 1 (control) had a 0% survival rate, mice in arm 2 (PD-1) had a 30% survival rate, and mice in arms 6, 7, and 8 had a 60-70% survival rate. Thus, at day 60, the mouse survival ratios (MSR 60 ) was about 2.0-2.3 (i.e., 60 / 30 and 70 / 30). Preferably, according to the present invention, the mouse survival ratio (MSR) was measured on day 26 after tumor implantation. 26 ) is at least 1.4, more preferably at least 1.6. Preferably, according to the invention, the mouse survival ratio (MSR) is at least 1.4, more preferably at least 1.6, when measured 28 days after tumor implantation. 28 ) is at least 2.0, more preferably at least 2.6. Preferably, according to the invention, the mouse survival ratio (MSR) is at least 2.0, more preferably at least 2.6, when measured 60 days after tumor implantation. 60 ) is at least 2.0, more preferably at least 2.3. Preferably, according to the invention, the mouse survival ratio measured at the time when untreated mice reach 0% survival or up to 60 days thereafter from tumor implantation is at least 1.4, at least 1.6, at least 2.0, at least 2.3, or at least 2.6. Typically, the combination therapy according to the invention, i.e., immunotherapeutic anti-cancer agent and glutamate modulating agent, will have an MSR of at least 2.0, more typically at least 2.3 (measured at day 60). 60 ) mouse survival ratio.

[0153] Example 2 The following illustrates an example of how the glutamate modulating agents of the present invention can be used in combination therapy with KEYTRUDA® (pembrolizumab), available from Merck & Co., Inc. (Whitehouse Station, NJ, USA). For additional information, see KEYTRUDA (pembrolizumab) for Injection, KEYTRUDA (pembrolizumab) Highlights of Prescribing Information for Intravenous Use, KEYTRUDA (pembrolizumab) Injection (uspi-mk3475-iv-1703r007) ("KEYTRUDA Package Insert").

[0154] According to the KETRUDA prescribing information, KEYTRUDA is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with: unresectable or metastatic melanoma; patients with metastatic NSCLC whose tumors have high PD-L1 expression [(Tumor Proportion Score (TPS) ≥ 50%)] as determined by an FDA-approved test who do not have EGFR or ALK genomic tumor aberrations and have not received prior systemic chemotherapy treatment for metastatic NSCLC; patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%) as determined by an FDA-approved test who have disease progression since platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations have had disease progression on FDA-approved treatment for these aberrations prior to receiving KEYTRUDA. Patients with recurrent or metastatic HNSCC who have disease progression since platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Adult and pediatric patients with refractory cHL or who have relapsed after three prior therapies. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

[0155] The Summary of Product Characteristics for KETRUDA published by the European Medicines Agency lists the following clinical trials, which were not performed by the applicant but are provided for illustrative purposes:

[0156] melanoma KEYNOTE-006: A controlled study in ipilimumab-naive melanoma patients. The safety and efficacy of pembrolizumab was studied in KEYNOTE-006, a multicenter, controlled phase III trial for the treatment of advanced melanoma in patients who had not previously been treated with ipilimumab. Patients were randomized (1:1:1) to receive pembrolizumab 10 mg / kg every 2 weeks (n=279) or every 3 weeks (n=277) or ipilimumab 3 mg / kg every 3 weeks (n=278). Patients with BRAF V600E mutant melanoma were not required to have received prior BRAF inhibitor treatment. Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with early evidence of disease progression were allowed to continue treatment until disease progression was confirmed. Tumor status was assessed at 12 weeks, then every 6 weeks until 48 weeks, and then every 12 weeks thereafter. Of the 834 patients, 60% were male, 44% were 65 years or older (median age was 62 years [range 18-89]), and 98% were white. 65% of patients had stage M1c disease, 9% had a history of brain metastases, 66% had not been previously treated, and 34% had received one prior treatment. 31% had an ECOG performance status of 1, 69% had an ECOG performance status of 0, and 32% had elevated LDH. BRAF mutations were reported in 302 (36%) patients. Of patients with BRAF-mutated tumors, 139 (46%) had been previously treated with a BRAF inhibitor. The primary efficacy outcome measures were progression-free survival (PFS; assessed by radiological and integrated oncology review [IRO] using Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcomes were overall response rate (ORR) and duration of response. Table 2 summarizes key efficacy measures in ipilimumab-naïve patients.

[0157] [Table 2]

[0158] According to the present invention, patients participating in such studies may be treated with a glutamate modulating agent, such as riluzole or its prodrug BHV-4157 (2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide) in combination therapy. The specific treatment regimen may be determined by one skilled in the art. However, for illustrative purposes, the following may be considered when designing a treatment regimen. The abbreviations used below are commonly known to those skilled in the art.

[0159] TIFF0007653398000008.tif214161

[0160] Treatment - Patients could be treated with daily oral BHV-4157 with IV treatment with pembrolizumab at pre-determined intervals, such as 1 week, 3 weeks, 5 weeks, 7 weeks, 9 weeks, and 11 weeks. The primary endpoints are the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BHV-4157. Secondary endpoints include: Objective response rate (ORR) Type, severity and frequency of adverse events Overall survival (OS), breakthrough survival rates at 1 and 2 years Duration of response in responding patients Time to progressive disease (PFS) Time until treatment fails Time to next treatment or death (TTNTD) No new metastases Correlative Science: Tumor microenvironment and peripheral blood changes in the following categories: TIL and PD-L1 expression Immune cell phenotype and gene expression Angiogenesis markers Metabolic effector molecules Exosome formation.

[0161] Once the above studies are completed, further studies can be conducted to determine efficacy, dosage refinement, side effects, etc., to identify useful treatments for patients receiving immuno-oncology therapy in conjunction with glutamate modulating agents.

[0162] Example 3 The following illustrates an example of how the glutamate modulators of the present invention can be used in combination therapy with OPDIVO® (nivolumab), available from Bristol-Myers Squibb Company, Princeton, NJ USA. For additional information, see Important Information for OPDIVO (nivolumab) Injection (1506US1700258-01-01) for intravenous use ("OPDIVO Package Insert").

[0163] According to the OPDIVO prescribing information, OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with: ·BRAF V600 wild-type unresectable or metastatic melanoma (as a single agent). ·BRAF V600 mutation-positive unresectable or metastatic melanoma (as a single agent). This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ·Unresectable or metastatic melanoma (in combination with ipilimumab). This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ·Metastatic non-small cell lung cancer and progression following platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations have had disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. ·Advanced renal cell carcinoma that has received prior antiangiogenic therapy. ·Classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplant brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ·Recurrent or metastatic head and neck squamous cell carcinoma with disease progression since platinum-based therapy. ·Locally advanced or metastatic urothelial carcinoma with disease progression during or after platinum-containing chemotherapy and with disease progression within 12 months of platinum-containing chemotherapy and neoadjuvant or adjuvant therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

[0164] The Summary of Product Characteristics for OPDIVO published by the European Medicines Agency lists the following clinical trials, which were not performed by the applicant but are provided for illustrative purposes:

[0165] Melanoma – Randomized Phase 3 Trial vs Dacarbazine (CA209066) The safety and efficacy of nivolumab 3 mg / kg for the treatment of advanced (unresectable or metastatic) melanoma was evaluated in a phase 3 randomized double-blind study (CA209066). The study included adult patients (≥18 years) with confirmed untreated stage III or IV BRAF wild-type melanoma and an ECOG performance-status score of 0 or 1. Patients with active autoimmune disease, ocular melanoma, or active brain and leptomeningeal metastases were excluded from the study. A total of 418 patients received either nivolumab (n=210) 3 mg / kg intravenously over 60 minutes every 2 weeks or dacarbazine (n=208) 1000 mg / m every 3 weeks. 2Patients were randomized to receive 100 mg / kg / day of chemotherapy or 100 mg / kg / day of chemotherapy. Randomization was stratified by tumor PD-L1 status and M stage (M0 / M1a / M1b vs. M1c). Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Treatment after disease progression was permitted for patients who had clinical benefit or no substantial adverse effects to study drug, as determined by the investigator. Tumor evaluations according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were performed 9 weeks after randomization and continued every 6 weeks for the first year and every 12 weeks thereafter. The primary efficacy outcome measure was overall survival (OS). Key secondary efficacy outcomes were investigator-assessed PFS and objective response rate (ORR). Baseline characteristics were well balanced between the two groups. The median age was 65 years (range: 18-87), 59% were male, and 99.5% were white. Most patients had an ECOG activity score of 0 (64%) or 1 (34%). 61% of patients had stage M1c disease at study entry. 74% of patients had cutaneous melanoma, 11% had mucosal melanoma; 35% of patients had PD-L1-positive melanoma (>5% tumor cell membrane expression). 16% of patients had prior adjuvant therapy; the most common adjuvant treatment was interferon (9%). 4% of patients had a history of brain metastases, and 37% of patients had baseline LDH levels above the ULN at study entry. Efficacy results are shown in Table 3.

[0166] [Table 3]

[0167] According to the present invention, patients participating in such studies may be treated with a glutamate modulating agent, such as riluzole or its prodrug BHV-4157 (2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide). Treatment regimens using glutamate modulating agents may be specified, for example, as described in Example 2.

[0168] Example 4 The following illustrates an example of how the glutamate modulating agents of the invention can be used in combination therapy with YERVOY® (ipilimumab), available from Bristol-Myers Squibb Company, Princeton, NJ USA. For additional information, see Important Notices for YERVOY (ipilimumab) Injection for Intravenous Use (1506US1700258-01-01) ("YERVOY Package Insert").

[0169] According to the YERVOY prescribing information, YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody indicated for the treatment of unresectable or metastatic melanoma. As the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes greater than 1 mm who have undergone complete resection, including total lymphadenectomy.

[0170] The Summary of Product Characteristics for YERVOY published by the European Medicines Agency lists the following clinical trials, which were not performed by the applicant but are provided for illustrative purposes:

[0171] MDX010-20 This double-blind, phase 3 study enrolled patients with advanced (unresectable or metastatic) melanoma who had previously been treated with a treatment regimen that included one or more of the following: IL-2, dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive ipilimumab 3 mg / kg plus investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg / kg monotherapy, or gp100 alone. Patients were randomized to receive ipilimumab 3 mg / kg plus investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg / kg monotherapy, or gp100 alone. *0201 type; this HLA type supports immune presentation of gp100. Patients were enrolled regardless of their baseline BRAF mutation status. Patients received four doses of ipilimumab every 3 weeks, as tolerated (induction therapy). Patients who showed a clear increase in tumor burden before the completion of the induction period continued induction therapy, as tolerated, if they showed sufficient activity indicators. Evaluation of tumor response to ipilimumab was performed approximately 12 weeks after the completion of induction therapy. Patients who developed PD after an initial clinical response (PR or CR) or SD (by modified WHO criteria) more than 3 months after the first tumor evaluation were given further treatment with ipilimumab (retreatment). The primary endpoint was OS in the ipilimumab + gp100 group versus the gp100 group. Key secondary endpoints were OS in the ipilimumab + gp100 group versus the ipilimumab monotherapy group, and in the ipilimumab monotherapy group versus the gp100 group. A total of 676 patients were randomized as follows: 137 to the ipilimumab monotherapy group, 403 to the ipilimumab + gp100 group, and 136 to the gp100 alone group. The majority received all four doses during induction. Thirty-two patients underwent retreatment: 8 in the ipilimumab monotherapy group, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Follow-up was up to 55 months. Baseline characteristics were well balanced between groups. Median age was 57 years. The majority of patients (71–73%) had stage M1c disease, and 37–40% of patients had elevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients had a history of previously treated brain metastases. The ipilimumab-containing treatment regimen demonstrated a statistically significant advantage in OS over the gp100 control group. The hazard ratio (HR) for the comparison of OS between ipilimumab monotherapy and gp100 was 0.66 (95% CI: 0.51, 0.87; p=0.0026).17 Subgroup analysis showed that the observed OS benefit was consistent within most subgroups of patients (M [metastatic] stage, previous interleukin 2, baseline LDH, age, sex, and type and number of previous therapies). However, for women over 50 years of age, there were limited data supporting an OS benefit of ipilimumab treatment. Thus, the efficacy of ipilimumab for women over 50 years of age is unclear. Because the subgroup analyses included only small numbers of patients, definitive conclusions cannot be drawn from these data. Median and estimated 1- and 2-year OS are shown in Table 4.

[0172] [Table 4]

[0173] In the ipilimumab 3 mg / kg monotherapy group, the median OS was 22 and 8 months for patients with SD and PD, respectively. At the time of this analysis, the median number of patients with CR or PR had not been reached. For patients requiring retreatment, the BORR was 38% (3 / 8 patients) in the ipilimumab monotherapy group and 0% in the gp100 group. Disease control rates (DCR) (defined as CR+PR+SD) were 75% (6 / 8 patients) and 0%, respectively. The limited number of patients in these analyses does not allow definitive conclusions to be drawn regarding the efficacy of ipilimumab retreatment. Development or maintenance of clinical activity after ipilimumab treatment was similar with or without the use of systemic corticosteroids.

[0174] According to the present invention, patients participating in such studies may be treated with a glutamate modulating agent, such as riluzole or its prodrug BHV-4157 (2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide). Treatment regimens using glutamate modulating agents may be specified, for example, as described in Example 2.

[0175] Example 5 The following illustrates an example of how the glutamate modulating agents of the present invention can be used in combination therapy with KEYTRUDA® (pembrolizumab), available from Merck & Co., Inc. (Whitehouse Station, NJ, USA). For additional information, see KEYTRUDA (pembrolizumab) for Injection, KEYTRUDA (pembrolizumab) Highlights of Prescribing Information for Intravenous Use, KEYTRUDA (pembrolizumab) Injection (uspi-mk3475-iv-1703r007) ("KEYTRUDA Package Insert").

[0176] The Summary of Product Characteristics for KETRUDA published by the European Medicines Agency lists the following clinical trials, which were not performed by the applicant but are provided for illustrative purposes:

[0177] NSCLC - KEYNOTE-010: A controlled study of patients with NSCLC previously treated with chemotherapy The safety and efficacy of pembrolizumab was studied in KEYNOTE-010, a multicenter, open-label, controlled trial for the treatment of advanced NSCLC in patients previously treated with platinum-containing chemotherapy. Patients had PD-L1 expression based on PDL1 IHC 22C3 pharmDxTM Kit with a TPS of ≥1%. Patients with EGFR activating mutations or ALK translocations also had disease progression on approved treatment for these mutations prior to administration of pembrolizumab. Patients received pembrolizumab at doses of 2 mg / kg (n=344) or 10 mg / kg (n=346) every 3 weeks until disease progression or unacceptable toxicity, or 75 mg / m every 3 weeks. 2 Patients were randomized (1:1:1) to receive docetaxel (n=343) at a dose of 0.01 mg / kg / day or 0.01 mg / kg / day. The study excluded patients with autoimmune disease; with a medical condition requiring immunosuppression; or who had received more than 30 Gy of thoracic irradiation within the past 26 weeks. Tumor status assessments were performed every 9 weeks. Baseline characteristics of the population included: median age 63 years (42% 65 years or older); 61% male; 72% white and 21% Asian, and 34% and 66% with ECOG activity indices 0 and 1, respectively. Disease characteristics were squamous (21%) and non-squamous (70%); M1 (91%); stable brain metastases (15%) and incidence of mutations EGFR (8%) or ALK (1%). Previous treatment included platinum doublet plans (100%); patients had received 1 (69%) or 2 or more (29%) lines of treatment. The primary efficacy measures were OS and PFS assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy measures were ORR and duration of response. Table 5 summarizes key efficacy measures for the overall population (TPS ≥ 1%) and for patients with TPS ≥ 50%.

[0178] [Table 5]

[0179] Efficacy results were similar for the pembrolizumab 2 mg / kg and 10 mg / kg arms. OS efficacy results were consistent regardless of tumor specimen age (new vs. archived) based on between-group comparisons. In subgroup analyses, reduced survival was observed with pembrolizumab compared with docetaxel for patients who were never smokers or had tumors with EGFR-activating mutations who had received at least platinum-based chemotherapy and a tyrosine kinase inhibitor; however, due to the small number of patients, definitive conclusions cannot be drawn from these data. The efficacy and safety of pembrolizumab in patients with tumors that do not express PD-L1 have not been established.

[0180] According to the present invention, patients participating in such studies may be treated with a glutamate modulating agent, such as riluzole or its prodrug BHV-4157 (2-amino-N-{[methyl({[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl}methyl)carbamoyl]methyl}acetamide). Treatment regimens using glutamate modulating agents may be specified, for example, as described in Example 2.

[0181] Throughout this application, various publications are referred to by author name and date, by patent number or patent application publication number. The disclosures of these publications are incorporated herein by reference in their entirety in order to more fully describe the state of the art known to those skilled in the art as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an admission that such reference is prior art to the present invention.

[0182] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims. For example, it is contemplated that combination therapy using glutamate modulating agents and immunotherapeutic agents can be used in accordance with the present invention to treat cancers other than the specific cancers described in the description and examples herein. Furthermore, glutamate modulating agents and immunotherapeutic agents other than those described in the description and examples herein can be used. Furthermore, any particular item in a list of items, or any subset group of items within a larger group of items, may be combined with any other particular item, item subset group of items, or larger group of items, regardless of whether there is a description herein identifying such combinations. The present application also includes the following aspects. [Aspect 1] 20. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a glutamate modulating agent and an immunotherapeutic anti-cancer agent. [Aspect 2] The method of embodiment 1, wherein the glutamate modulator is an agent that promotes the regulation, regulation, attenuation or enhancement of (i) an ionotropic glutamate receptor; (ii) a metabotropic glutamate receptor; or (iii) a glutamate transporter. [Aspect 3] The method of embodiment 1, wherein the glutamate modulating agent is an agent that inhibits glutamate release. [Aspect 4] The method of embodiment 1, wherein the glutamate modulating agent is an agent that regulates, modulates, attenuates or enhances glutamate or glutamine metabolism. [Aspect 5] The method of embodiment 2, wherein the ionotropic glutamate receptor is selected from N-methyl-D-aspartate ("NMDA"), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ("AMPA"), and kainate. [Aspect 6] 3. The method of embodiment 2, wherein the metabotropic glutamate receptor is one or more of a type 1 receptor selected from mGluR1 and mGluR5; a type II receptor selected from mGluR2 and mGluR3; or a type III receptor selected from mGluR4, mGluR6, mGluR7, and mGluR8. [Aspect 7] The method of embodiment 2, wherein the glutamate transporter is expressed in glia or neurons. [Aspect 8] The method of embodiment 1, wherein the glutamate modulating agent is selected from riluzole, memantine, n-acetylcysteine, amantadine, topiramate, pregabalin, lamotrigine, ketamine, s-ketamine, AZD8108, AZD6765 (lanicemine), BHV-4157 (trigriluzole), dextromethorphan, AV-101, CERC-301, GLY-13, and pharma- ceutically acceptable salts, prodrugs, or analogs thereof. [Aspect 9] 5. The glutamate modulator having the formula: [ka] The method of embodiment 8, comprising: [Aspect 10] The method of embodiment 1, wherein the immunotherapeutic anti-cancer agent is selected from an antibody, a peptide, a protein, a small molecule, an adjuvant, a cytokine, an oncolytic virus, a vaccine, a bispecific molecule, and a cellular therapeutic agent. [Aspect 11] The method of embodiment 10, wherein the immunotherapeutic anti-cancer agent is a checkpoint inhibitor. [Aspect 12] The method of embodiment 11, wherein the checkpoint inhibitor is an inhibitor of a checkpoint receptor selected from PD-1, PD-L1, and CTLA-4. [Aspect 13] The method of embodiment 12, wherein the inhibitor of PD-1 is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, and pidilizumab. [Aspect 14] The method of embodiment 12, wherein the inhibitor of PD-L1 is an anti-PD-L1 antibody selected from BMS-936559, durvalumab, atezolizumab, avelumab, and MDX-1105. [Aspect 15] The method of embodiment 12, wherein the inhibitor of PD-L1 is a peptide. [Aspect 16] The method of embodiment 12, wherein the inhibitor of CTLA-4 is an anti-CTLA-4 antibody selected from ipilimumab and tremelimumab. [Aspect 17] Glutamate-modulating agents and immunotherapeutic anticancer agents are shown to have a 60-day mouse survival ratio (MSR) of at least 2.0. 60 2. The method of embodiment 1, wherein the method is capable of providing a [Aspect 18] A method for modulating glutamate in a patient being treated with an immunotherapeutic anti-cancer agent, comprising contacting a glutamate receptor or a glutamate transporter in the patient with a glutamate modulating agent proximal to the treatment with the immunotherapeutic anti-cancer agent. [Aspect 19] The method of embodiment 18, wherein the glutamate modulating agent is riluzole. [Aspect 20] The method of embodiment 19, wherein riluzole is administered intravenously, intramuscularly, parenterally, sublingually, intranasally, or orally. [Aspect 21] The method of embodiment 20, wherein riluzole is administered in the form of a prodrug. [Aspect 22] The prodrug has the formula:

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Claims

1. A pharmaceutical combination for the treatment of cancer in a patient in need thereof, comprising a glutamate modulating agent and an immunotherapeutic anti-cancer agent, 5. The glutamate modulator having the formula: 【Chemistry 1】 [In the formula, R 23 is H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , C.H. 2 CCH, CH(CH 3 ) 2 , C.H. 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C.H. 2 O.H., C.H. 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , C.H. 2 Ph, CH 2 (Cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 N.H. 2 , (CH 2 ) 3 NHC(NH 2 )NH,CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, C.H. 2 CH 2 CO 2 H, C.H. 2 CONH 2 , and C.H. 2 CH 2 CONH 2 selected from the group consisting of or an enantiomer, diastereomer, hydrate, solvate, pharma- ceutically acceptable salt, or complex thereof; The immunotherapy anticancer drug is a combination of pembrolizumab and nivolumab; Combination medicines.

2. 5. The glutamate modulator having the formula: 【Chemistry 2】 2. The pharmaceutical combination according to claim 1, which has the formula:

3. Glutamate modulating agents and immunotherapeutic anti-cancer agents are shown to have a mouse survival ratio (MSR) of at least 2.0 at day 60. 60 3. The pharmaceutical combination according to claim 1 or 2, which is capable of providing

4. 1. A medicament for modulating glutamate in a patient being treated with an immunotherapeutic anticancer agent, comprising a glutamate modulating agent, the medicament being administered such that the glutamate modulating agent comes into contact with a glutamate receptor or a glutamate transporter in the patient proximal to the treatment with the immunotherapeutic anticancer agent; 5. The glutamate modulator having the formula: 【Chemistry 3】 [In the formula, R 23 is H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , C.H. 2 CCH, CH(CH 3 ) 2 , C.H. 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C.H. 2 O.H., C.H. 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , C.H. 2 Ph, CH 2 (Cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 N.H. 2 , (CH 2 ) 3 NHC(NH 2 )NH,CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, C.H. 2 CH 2 CO 2 H, C.H. 2 CONH 2 , and C.H. 2 CH 2 CONH 2 selected from the group consisting of or an enantiomer, diastereomer, hydrate, solvate, pharma- ceutically acceptable salt, or complex thereof; The immunotherapy anticancer drug is a combination of pembrolizumab and nivolumab; Medicine.

5. 5. The method of claim 4, wherein the contacting of the glutamate receptor or transporter with the glutamate modulator is performed before, simultaneously with or after treatment with an immunotherapeutic anti-cancer agent.

6. The method of claim 4 or 5, wherein the near time is within one week of treatment with an immunotherapeutic anticancer agent.

7. The method of any one of claims 4 to 6, wherein the glutamate modulator is administered intravenously, intramuscularly, parenterally, sublingually, nasally, or orally.

8. 5. The glutamate modulator having the formula: 【Chemistry 4】 The pharmaceutical composition according to any one of claims 4 to 7, which has the formula:

9. A medicament for sensitizing a patient suffering from cancer who is being treated with an immunotherapeutic anticancer agent, comprising a glutamate modulating agent, the medicament being administered to the patient in close proximity to the treatment with the immunotherapeutic anticancer agent; 5. The glutamate modulator having the formula: 【Chemistry 5】 [In the formula, R 23 is H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , C.H. 2 CCH, CH(CH 3 ) 2 , C.H. 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C.H. 2 O.H., C.H. 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , C.H. 2 Ph, CH 2 (Cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 N.H. 2 , (CH 2 ) 3 NHC(NH 2 )NH,CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, C.H. 2 CH 2 CO 2 H, C.H. 2 CONH 2 , and C.H. 2 CH 2 CONH 2 selected from the group consisting of or an enantiomer, diastereomer, hydrate, solvate, pharma- ceutically acceptable salt, or complex thereof; The immunotherapy anticancer drug is a combination of pembrolizumab and nivolumab; Medicine.

10. The pharmaceutical agent of claim 9, wherein the sensitization promotes an enhanced antitumor effect.

11. The pharmaceutical agent according to claim 9 or 10, wherein the enhanced antitumor effect is measured by an increase in the objective response rate or an increase in the duration of response in a patient.

12. The pharmaceutical agent according to any one of claims 9 to 11, wherein the enhanced antitumor effect promotes an increase in overall survival of the patient.

13. The pharmaceutical agent according to any one of claims 9 to 12, wherein the overall survival is increased to at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after the first administration of the immunotherapeutic anticancer agent.

14. The pharmaceutical agent of any one of claims 9 to 13, wherein the overall survival is at least about 1.1 times, at least about 1.2 times, at least about 1.3 times, at least about 1.4 times, at least about 1.5 times, at least about 2.0 times, at least about 3.0 times, or at least about 3.0 times the overall survival of patients treated with a therapeutically effective amount of an immunotherapeutic anti-cancer agent but not treated with a glutamate modulating agent.

15. 1. A medicament for improving response in a patient suffering from cancer being treated with an immunotherapeutic anticancer agent, comprising a glutamate modulating agent, 5. The glutamate modulator having the formula: 【Chemistry 6】 [In the formula, R 23 is H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , C.H. 2 CCH, CH(CH 3 ) 2 , C.H. 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C.H. 2 O.H., C.H. 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , C.H. 2 Ph, CH 2 (Cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 N.H. 2 , (CH 2 ) 3 NHC(NH 2 )NH,CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, C.H. 2 CH 2 CO 2 H, C.H. 2 CONH 2 , and C.H. 2 CH 2 CONH 2 selected from the group consisting of or an enantiomer, diastereomer, hydrate, solvate, pharma- ceutically acceptable salt, or complex thereof; The immunotherapy anticancer drug is a combination of pembrolizumab and nivolumab; Medicine.

16. The pharmaceutical composition of claim 15, wherein the improved response is one or more of overall survival, quality of life, overall response rate, duration of response, progression-free survival, patient-reported outcome, minimal residual disease, or immune response.

17. The combination pharmaceutical according to any one of claims 1 to 3, or the pharmaceutical according to any one of claims 4 to 16, which is further used in combination with treatment with an antibody selected from an anti-LAG3 antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti-TGFp antibody, an anti-IL-10 antibody, an anti-B7-H4 antibody, an anti-Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD20 antibody, an anti-CD27 antibody, an anti-GITR antibody, an anti-OX40 antibody, or a combination thereof.

18. The combination pharmaceutical according to any one of claims 1 to 3, or the pharmaceutical according to any one of claims 4 to 16, further used in conjunction with treatment with radiation therapy, chemotherapy, a vaccine, a cytokine, a tyrosine kinase inhibitor, an anti-VEGF inhibitor, an IDO inhibitor, an IDO1 inhibitor, a TGF-β inhibitor, or a combination thereof.

19. Cancers include melanoma, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia), juvenile or adult leukemia, pediatric or adult leukemia, or pediatric or adult leukemia. The pharmaceutical combination according to any one of claims 1 to 3, the pharmaceutical according to any one of claims 4 to 16, or the pharmaceutical combination or pharmaceutical according to claim 17 or 18, selected from childhood solid tumors, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer (including cancer induced by asbestos), and combinations thereof.

20. A kit for administering an immunotherapeutic anti-cancer agent together with a glutamate modulating agent in the use of a pharmaceutical combination according to any one of claims 1 to 3, a pharmaceutical composition according to any one of claims 4 to 16, or a pharmaceutical combination or pharmaceutical composition according to any one of claims 17 to 19 in the treatment of a patient suffering from cancer, comprising (a) an immunotherapeutic anticancer agent; and (b) Instructions A kit comprising:

5. The glutamate modulator having the formula: 【Chemistry 7】 [In the formula, R 23 is H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , C.H. 2 CCH, CH(CH 3 ) 2 , C.H. 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C.H. 2 O.H., C.H. 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , C.H. 2 Ph, CH 2 (Cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 N.H. 2 , (CH 2 ) 3 NHC(NH 2 )NH,CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, C.H. 2 CH 2 CO 2 H, C.H. 2 CONH 2 , and C.H. 2 CH 2 CONH 2 selected from the group consisting of or an enantiomer, diastereomer, hydrate, solvate, pharma- ceutically acceptable salt, or complex thereof; The immunotherapy anticancer drug is a combination of pembrolizumab and nivolumab; kit.

21. A kit for administering a glutamate modulating agent together with an immunotherapeutic anti-cancer agent in the use of a pharmaceutical combination according to any one of claims 1 to 3, a pharmaceutical combination according to any one of claims 4 to 16, or a pharmaceutical combination or pharmaceutical according to any one of claims 17 to 19 in the treatment of a patient suffering from cancer, comprising (a) a glutamate modulator; and (b) Instructions A kit comprising:

5. The glutamate modulator having the formula: 【Chemistry 8】 [In the formula, R 23 is H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , C.H. 2 CCH, CH(CH 3 ) 2 , C.H. 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C.H. 2 O.H., C.H. 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , C.H. 2 Ph, CH 2 (Cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 N.H. 2 , (CH 2 ) 3 NHC(NH 2 )NH,CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, C.H. 2 CH 2 CO 2 H, C.H. 2 CONH 2 , and C.H. 2 CH 2 CONH 2 selected from the group consisting of or an enantiomer, diastereomer, hydrate, solvate, pharma- ceutically acceptable salt, or complex thereof; The immunotherapy anticancer drug is a combination of pembrolizumab and nivolumab; kit.

22. 5. The glutamate modulator having the formula: 【Chemistry 9】 The kit of claim 21 , comprising:

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