Methods for treating colon cancer with compositions comprising amlexanox and immune checkpoint inhibitors

Abstract

Disclosed herein are compositions and methods for treating cancer in a subject. In some embodiments, the methods involve generating an immune response in an individual by inducing the expression of neoantigens on the surface of abnormal (such as proliferative) cells. In one embodiment, a method of treating cancer in a subject includes administering amlexanox in combination with immune modulators, such as checkpoint inhibitors, immune co-stimulatory molecules, TLR agonists, and TNFR superfamily agonists. In one embodiment, the checkpoint inhibitors are selected from antibodies against PD-1, PD-L1, and CTLA-4.

1 . A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of amlexanox and a therapeutically effective amount of at least one checkpoint inhibitor, wherein the cancer is melanoma. 
     
     
         2 . The method of  claim 1 , wherein the at least one checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-A2AR antibodies, anti-KIR antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, and combinations thereof. 
     
     
         3 . The method  claim 1 , wherein the method comprises administering amlexanox in combination with anti-PD-1 and anti-CTLA-4 antibodies. 
     
     
         4 . The method  claim 1 , wherein the method comprises administering amlexanox in combination with anti-PD-L1 and anti-CTLA-4 antibodies. 
     
     
         5 . The method of  claim 1 , wherein amlexanox is administered at a dose from about 1 mg/kg to 50 mg/kg daily. 
     
     
         6 . The method of  claim 1 , wherein the checkpoint inhibitor is administered at a dose from about 3 mg/kg to about 10 mg/kg every 3 days. 
     
     
         7 . The method of  claim 1 , wherein route of administration is selected from the group consisting of oral, topical, subcutaneous, intramuscular, intraperitoneal, intracavity, intrathecal, transdermal, and intravenous injection. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , further comprising administering an anti-cancer agent selected from the group consisting of tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anasfrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfarnide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, Irinotecan, topotecan, an epothilone, gefitinib, erlotinib, sorafenib, angiogenesis inhibitors, EGF inhibitors, VEGF inhibitors, CDK inhibitors, cytokines, Her1 and Her2 inhibitors, and monoclonal antibodies. 
     
     
         10 . The method of  claim 1 , further comprising administering immune modulators selected from immune co-stimulatory molecules, TLR agonists, TNFR superfamily agonists, cyclic dinucleotides, T-cell agonists, cytokines, chemokines, oncolytic virus, and combination thereof. 
     
     
         11 . The method of  claim 1 , further comprising administering epigenetic modulatory compounds selected from vorinostat, romidepsin, decitabine, 5-azocytidine, panobinostat, belinostat, and combination thereof. 
     
     
         12 . A method of killing a cancer cell comprising contacting the cancer cell with a composition comprising amlexanox in combination with at least one checkpoint inhibitor. 
     
     
         13 . The method of  claim 12 , wherein the at least one checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-A2AR antibodies, anti-KIR antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, and combinations thereof. 
     
     
         14 .- 16 . (canceled) 
     
     
         17 . A method of generating an immune response in an individual by inducing expression of a neoantigen on a surface of a cancer cell comprising administering a therapeutically effective amount of amlexanox in combination with at least one checkpoint inhibitor. 
     
     
         18 . The method of  claim 17 , wherein the at least one checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-A2AR antibodies, anti-KIR antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, and combinations thereof. 
     
     
         19 . The method  claim 17 , wherein the method comprises administering amlexanox in combination with anti-PD-1 and anti-CTLA-4 antibodies. 
     
     
         20 . The method  claim 17 , wherein the method comprises administering amlexanox in combination with anti-PD-L1 and anti-CTLA-4 antibodies. 
     
     
         21 . The method of  claim 17 . wherein amlexanox is administered at a dose from about 1 mg/kg to 50 mg/kg daily. 
     
     
         22 . The method of  claim 17 , wherein the checkpoint inhibitor is administered at a dose from about 3 mg/kg to about 10 mg/kg every 3 days. 
     
     
         23 .- 25 . (canceled)