Compositions and Methods for Cancer Immunotherapy

Abstract

The invention relates to immunotherapeutic compounds and to methods for stimulating an immune response in a subject individual at risk for developing cancer, diagnosed with a cancer, in treatment for cancer, or in post-therapy recovery from cancer or the compounds of the invention can be administered as a prophylactic to a subject individual to prevent or delay the development of cancer.

1 . A composition, comprising:
 at least one immunotherapeutic agent selected from one or more cancer antigens; one or more antigens derived from a virus associated with cancer; one or more anti-cancer antibodies; and one or more anti-idiotypic antibodies to an anti-cancer antibody; and,   one or more compounds selected from formulae (I), (II), (III), (IV), and (V) and/or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, amorphous solid thereof, or any combination thereof.   
     
     
         2 . The composition of  claim 1 , wherein the immunotherapeutic agent is one or more cancer antigens. 
     
     
         3 . The composition of  claim 2 , wherein the cancer antigen is MUC-1. 
     
     
         4 . The composition of  claim 2 , wherein the cancer antigen is selected from the group consisting of mutant B-raf, HER-2/neu, EGFR (variants 1-4), VEGFR (variants 1-2), PSA, PSMA, GP-100, CEA, CA 19.9, MART-1, K-ras, N-ras, H-ras, and p53. 
     
     
         5 . The composition of  claim 1 , wherein the antigen derived from a virus associated with cancer is human papilloma virus (HPV); hepatitis B or C virus (HBV or HCV); Epstein-Barr virus (EBV); human herpes virus-8 (HHV-8), HTLV-1, or HTLV-2. 
     
     
         6 . The composition of  claim 1 , wherein the anti-cancer antibody is trastuzumab, bevacizumab, rituximab, pertuzumab, cetuximab, IMC-1C11, BEXXAR®, ZEVALIN®, EMD 7200, SGN-30, SGN-15, SGN-30, SGN-40, SGN-35, or SGN-17/19. 
     
     
         7 . The composition of  claim 1 , wherein the anti-idiotypic antibody recognizes the antigen-binding site of an antibody to MUC-1, mutant B-raf, HER-2/neu, EGFR (variants 1-4), VEGFR (variants 1-2), PSMA, GP-100, CEA, CA 19.9, MART-1, K-ras, N-ras, H-ras, or p53. 
     
     
         8 . The composition of  claim 1 , wherein the compound is selected from ER 803022, ER 803058, ER 803732, ER 804053, ER 804058, ER 804059, ER 804442, ER 804680, ER 804764, ER 112066, and ER 804057, and/or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, amorphous solid thereof, or any combination thereof. 
     
     
         9 . The composition of  claim 8  wherein the compound is ER 804057 and/or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, amorphous solid thereof, or any combination thereof. 
     
     
         10 . The composition of  claim 1 , wherein the immunotherapeutic agent is one or more cancer antigens and the composition further comprises a second immunotherapeutic agent. 
     
     
         11 . A method for stimulating an immune response in a subject individual, the method comprising the steps of:
 administering to the individual at least one immunotherapeutic agent selected from one or more cancer antigens; one or more viral derived antigen associated with cancer; one or more anti-cancer antibodies; and one or more anti-idiotypic antibodies to an anti-cancer antibody; and   administering to the individual one or more compound selected from formulae (I), (II), (III), (IV) and (V) and/or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, amorphous solid thereof, or any combination thereof.   
     
     
         12 . The method of  claim 10 , wherein the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) are administered at about the same time. 
     
     
         13 . The method of  claim 11 , wherein the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) are administered separately. 
     
     
         14 . The method of  claim 11 , wherein the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) is administered to a subject individual at risk for developing cancer, diagnosed with a cancer, in treatment for cancer, or in post-therapy recovery from cancer. 
     
     
         15 . The method of  claim 14 , wherein the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) is administered therapeutically in combination with a surgical procedure to remove or reduce the size of a cancer tumor, radiation therapy, chemotherapy, and/or ablation therapy. 
     
     
         16 . The method of  claim 14 , wherein the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) is administered therapeutically to stabilize a tumor by preventing or slowing the growth of the existing cancer, to prevent the spread of a tumor or of metastases, to reduce the tumor size, to prevent the recurrence of treated cancer, or to eliminate cancer cells not killed by earlier treatments. 
     
     
         17 . The method of  claim 13 , wherein the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) are administered in combination with cancer therapies. 
     
     
         18 . The method of  claim 17 , wherein the cancer therapy is dendritic cell therapy, chemokines, cytokines, tumor necrosis factors (e.g., TNF-α), chemotherapeutic agents (e.g., adenosine analogs (e.g., cladribine, pentostatin), alkyl sulfanates (e.g., busulfan)), anti-tumoral antibiotics (e.g., bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, mitomycin), aziridines (e.g., thiotepa), camptothecin analogs (e.g., irinotecan, topotecan), cryptophycins (e.g., cryptophycin 52, cryptophicin 1), dolastatins (e.g., dolastatin 10, dolastatin 15), enedyine anticancer drugs (e.g., esperamicin, calicheamicin, dynemicin, neocarzinostatin, neocarzinostatin chromophore, kedarcidin, kedarcidin chromophore, C-1027 chromophore, and the like), epipodophyllotoxins (e.g., etoposide, teniposide), folate analogs (e.g., methotrexate), maytansinoids (e.g., maytansinol and maytansinol analogues), microtubule agents (e.g., docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine), nitrogen mustards (e.g., chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan), nitrosoureas (e.g., carmustine, lamustine, streptoxacin), nonclassic alkylators (e.g., altretamine, dacarbazine, procarbazine, temozolamide), platinum complexes (e.g., carboplatin, cisplatin), purine analogs (e.g., fludarabine, mercaptopurine, thioguanine), pyrimidine analogs (e.g., capecitabine, cytarabine, depocyt, floxuridine, fluorouracil, gemcitabine), substituted ureas (e.g., hydroxyurea)]; anti-angiogenic agents (e.g., canstatin, troponin I,), biologic agents (e.g., ZD 1839, virulizin and interferon), antibodies and fragments thereof (e.g., anti EGFR, anti-HER-2/neu, anti-KDR, IMC-C225), anti-emetics (e.g., lorazepam, metroclopramide, and domperidone), epithelial growth factor inhibitors (e.g., transforming growth factor beta 1), anti-mucositic agents (e.g., dyclonine, lignocaine, azelastine, glutamine, corticoid steroids and allopurinol), anti-osteoclastic agents (e.g., bisphosphonates {e.g., etidronate, pamidronate, ibandronate, and osteoprotegerin}), hormone regulating agents (e.g., anti-androgens, LHRH agonists, anastrozole, tamoxifen), hematopoietic growth factors, anti-toxicity agents (e.g., amifostine) and mixtures of two or more thereof. 
     
     
         19 . The method of  claim 11 , wherein the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) is administered prophylactically to the subject individual to prevent or delay the development of cancer. 
     
     
         20 . The method of  claim 11 , further comprising administering an immunostimulatory compound. 
     
     
         21 . The method of  claim 20 , wherein said immunostimulatory compound is a toll like receptor (TLR) agonist (e.g., TLR4, TLR7, TLR9), N-acetylmuramyl-L-alanine-D-isoglutamine (MDP), lipopolysaccharides (LPS), genetically modified and/or degraded LPS, alum, glucan, colony stimulating factors (e.g., EPO, GM-CSF, G-CSF, M-CSF, pegylated G-CSF, SCF, IL-3, IL6, PIXY 321), interferons (e.g., γ-interferon, α-interferon), interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-18), MHC Class II binding peptides, saponins (e.g., QS21), unmethylated CpG sequences, 1-methyl tryptophan, arginase inhibitors, cyclophosphamide, or antibodies that block immunosuppressive functions (e.g., anti-CTLA4 antibodies), or mixtures of two or more thereof.