Methods and pharmaceutical composition for the treatment of cancer

Abstract

The present invention relates to methods and pharmaceutical composition for the treatment of cancer. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen for cancer, the method comprising: administering a pharmaceutically effective amount of a TNFα blocking agent to a subject in combination with the immune checkpoint inhibitor.

1 . A method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen for cancer, the method comprising: co-administering a pharmaceutically effective amount of a tumor necrosis factor-alpha (TNFα) blocking agent to a subject in combination with the immune checkpoint inhibitor. 
     
     
         2 . A method of treating cancer in a subject in need thereof, comprising co-administering to the subject a therapeutically effective amount of a combination of
 an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an antibody inhibitor of programmed cell death protein-1 (PD-1) selected from the group consisting of nivolumab and pembrolizumab, with   a tumor necrosis factor-alpha(TNFα) blocking agent, wherein the TNFα blocking agent is an antibody having specificity for TNFα or TNFα receptor 1 (TNFR1) selected from the group consisting of certolizumab, certolizumab pegol, etanercept, infliximab, adalimumab, and golimumab,   wherein said cancer is selected from the group consisting of melanoma, breast cancer and lung cancer, and   wherein said therapeutic efficacy is indicated by regression of a tumor of the cancer.   
     
     
         3 . The method of  claim 1  wherein the subject suffers from a cancer selected from the group consisting of Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman's Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget's disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer, Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma, Granulosa cell tumor, Hairy Cell Leukemia, Hairy cell leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemangioblastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigo maligna melanoma, Leukemia, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant, Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplastic Disease, Myelodysplasia, Syndromes, Myeloid leukemia, Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, non-small cell lung cancer (NSCLC) which coexists with chronic obstructive pulmonary disease (COPD), Ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath, meningioma, Oral Cancer, Oral cancer, Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget's disease of the breast, Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonary blastema, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma, Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-cell acute, lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Vemer Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof. 
     
     
         4 . The method of  claim 1  wherein the cancer is a melanoma. 
     
     
         5 . The method of  claim 1  wherein the cancer is a melanoma resistant to BRAF inhibitors. 
     
     
         6 . The method of  claim 1  wherein the TNFα blocking agent is a soluble TNFα receptor or an antibody having specificity for TNFα or for TNFα receptor  1 . 
     
     
         7 . The method of  claim 1  wherein the TNFα blocking agent is selected from the group consisting of Etanercept (Enbrel®), Infliximab (Remicade®), Adalimumab (Humira®), Certolizumab pegol (Cimzia®), and golimumab (Simponi®). 
     
     
         8 . The method of  claim 1  wherein the immune checkpoint inhibitor is a PD-1 inhibitor. 
     
     
         9 . The method of  claim 1  wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of anti-CTLA4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-TIM-3 antibodies, anti-LAG3 antibodies, anti-B 7 H3 antibodies, anti-B7H4 antibodies, anti-BTLA antibodies, and anti-B7H6 antibodies. 
     
     
         10 . A method of preventing tumor escape in a subject treated with a PD-1 inhibitor comprising administering to the subject a therapeutically effective amount of a TNFα blocking agent. 
     
     
         11 . The method of  claim 10  wherein the tumor escaped escape is induced by the expression of TIM-3. 
     
     
         12 . The method of  claim 10  wherein the tumor escape is induced by the expression of TIM-3 and PD-1 or PD-L1. 
     
     
         13 . The method of  claim 11  which comprises i) determining the expression level of TIM-3 in a tumor tissue sample obtained from the subject, iii) comparing the expression level determined at step i) with a predetermined reference value and iv) co-administering to the subject a therapeutically effective amount of a PD-1 inhibitor and a TNFα blocking agent. 
     
     
         14 . A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective combination of a multispecific antibody comprising at least one binding site that specifically binds to an immune checkpoint protein and at least one binding site that specifically binds to TNFα or a receptor for TNFα. 
     
     
         15 . The method of  claim 14 , wherein the immune checkpoint protein is a PD-1 molecule. 
     
     
         16 . The method of  claim 14 , wherein the receptor for TNFα Fα is TNFR1 or TNFR2. 
     
     
         17 . A method of treating cancer in a subject in need thereof, comprising:
 co-administering to the subject a therapeutically effective amount of a combination of   at least one immune checkpoint inhibitor selected from the group consisting of an antibody inhibitor of programmed cell death protein-1 (PD-1), nivolumab, pembrolizumab, an antibody inhibitor of cytotoxic T lymphocyte associated protein-4 (CTLA-4), ipilimumab and pemgrolizumab; with   a tumor necrosis factor-alpha (TNFα) blocking agent to wherein the TNFα blocking agent is an antibody having specificity for TNFα or TNFα receptor 1 (TNFR1) selected from the group consisting of certolizumab, certolizumab pegol, etanercept, infliximab, adalimumab, and golimumab,   wherein therapeutic efficacy is indicated by regression of a tumor of the cancer.   
     
     
         18 . The method of  claim 17 , wherein two immune checkpoint inhibitors are co-administered with the TNFα blocking agent. 
     
     
         19 . The method of  claim 17 , wherein the antibody inhibitor of PD-1 is nivolimab. 
     
     
         20 . The method of  claim 17 , wherein the antibody inhibitor of CTLA-4 is ipilimumab. 
     
     
         21 . The method of  claim 17 , wherein the TNFα blocking agent is infliximab. 
     
     
         22 . The method of  claim 17 , wherein the TNFα blocking agent is certolizumab. 
     
     
         23 . The method of  claim 17 , wherein the cancer is selected from the group consisting of breast cancer, melanoma and lung cancer. 
     
     
         24 . The method of  claim 17 , wherein the cancer is melanoma.