Methods of treatment and related compositions

Abstract

The present invention relates to methods of treating a disease characterised by aberrant cell proliferation (e.g., a cancer) in a human subject in need thereof. In particular, the present invention relates to treating the above conditions by administering a therapeutically effective amount of at least one agent that increases activation of a receptor of at least one type II interferon and/or type I interferon, and administering to the subject at least one agent that inhibits the Hedgehog (Hh) signalling pathway (e.g., Vismodegib). Also provided are pharmaceutical compositions, including controlled release pharmaceutical compositions, containing at least one agent that increases activation of a receptor of at least one type II interferon and/or type I interferon (e.g., a checkpoint inhibitor), an inhibitor of Hh signalling pathway, and a controlled release matrix such as a SiO2 matrix gel.

1 . A method of treating a subject suffering from a cancer, the method comprising administering to the subject a therapeutically effective amount of:
 (i) at least one agent that increases activation of a receptor of at least one type II interferon and/or type I interferon; and   (ii) at least one agent that inhibits the Hedgehog (Hh) signalling pathway.   
     
     
         2 . (canceled) 
     
     
         3 . The method according to  claim 1 , wherein the subject is a human. 
     
     
         4 . The method according to  claim 1 , wherein that at least one agent in (i) is a type II interferon and/or type I interferon, or a polynucleotide encoding a type II interferon and/or type I interferon, or an agonist for a receptor of at least one type II interferon and/or type I interferon. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The method according to  claim 1 , wherein the at least one agent in (i) comprises one or more checkpoint inhibitors. 
     
     
         8 - 19 . (canceled) 
     
     
         20 . The method according to  claim 1 , wherein (i) is a recombinant virus for expression of interferon gamma. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . The method according to  claim 20 , wherein the recombinant virus is an adenovirus, an adeno-associated virus (AAV), a herpes simplex virus (HSV), or a lentivirus. 
     
     
         26 . The method according to  claim 25 , wherein the recombinant virus is an adenovirus or lentivirus. 
     
     
         27 - 30 . (canceled) 
     
     
         31 . The method according to  claim 1 , wherein the at least one agent in (i) is administered systemically, intralesionally, or topically. 
     
     
         32 - 35 . (canceled) 
     
     
         36 . The method according to  claim 1 , wherein the inhibitor of the Hh signalling pathway is selected from the group consisting of: Vismodegib, Sonidegib, Saridegib, LEQ-506, Taladegib, Itraconazole, Glasdegib, Jervine, CUR61414, BMS-833923, TAK-441, MRT-92, GDC-0449, HH-13, GANT61, and HH-20. 
     
     
         37 . (canceled) 
     
     
         38 . The method according to  claim 1 , wherein the small molecule inhibitor of the Hh signalling pathway is administered at a dose of about 150 mg to about 500 mg per day. 
     
     
         39 - 53 . (canceled) 
     
     
         54 . The method according to  claim 1 , wherein administration of (i) the at least one agent that increases activation of a receptor of at least one type II interferon and/or type I interferon; and (ii) the agent that inhibits the Hedgehog (Hh) signalling pathway is performed separately during a first dosing period. 
     
     
         55 . The method according to  claim 54 , wherein, during the first dosing period, (ii) is administered after beginning administration of (i). 
     
     
         56 . (canceled) 
     
     
         57 . The method according to  claim 54 , wherein, during the first dosing period, (ii) is administered before administration of (i). 
     
     
         58 . (canceled) 
     
     
         59 . The method according to  claim 1 , wherein administration of (i) the at least one agent that increases activation of a receptor of at least one type II interferon and/or type I interferon; and (ii) the agent that inhibits the Hedgehog (Hh) signalling pathway are co-administered during a first dosing period. 
     
     
         60 . (canceled) 
     
     
         61 . The method according to  claim 1 , wherein (i), (ii), or both (i) and (ii) are administered multiple times during a first dosing period. 
     
     
         62 . The method according to  claim 54 , further comprising at least a second dosing period. 
     
     
         63 . The method according to  claim 1 , wherein the subject is treated over a period of about one week to about twelve weeks. 
     
     
         64 . The method according to  claim 63 , wherein the dose of (ii) administered or treatment period with (ii) in combination with (i) is limited to avoid induction of at least one adverse event associated with treatment with (ii) alone. 
     
     
         65 - 66 . (canceled) 
     
     
         67 . The method according to  claim 1 , wherein the cancer is selected from the group consisting of: basal cell carcinoma, melanoma, lymphoma, squamous cell carcinoma, Merkel cell carcinoma, lung cancer, prostate cancer, sarcomas, medulloblastomas, cancers with desmoplastic stromas, colorectal cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, mesothelioma, mesenchymal cancer, epithelial cancer, and adenocarcinomas. 
     
     
         68 . The method according to  claim 67 , wherein the cancer is a basal cell carcinoma (BCC). 
     
     
         69 . (canceled) 
     
     
         70 . The method according to  claim 1 , wherein the cancer is a recurrent cancer or a relapsing cancer. 
     
     
         71 - 79 . (canceled) 
     
     
         80 . A pharmaceutical composition for use in treatment of a disease characterised by aberrant cell proliferation, the pharmaceutical composition comprising:
 (i) at least one agent that increases activation of a receptor of at least one type II interferon and/or type I interferon; and   (ii) at least one agent which inhibits the Hedgehog (Hh) signalling pathway.   
     
     
         81 - 83 . (canceled) 
     
     
         84 . A pharmaceutical composition for use in treatment of a disease characterised by aberrant cell proliferation, the pharmaceutical composition comprising:
 (i) at least one checkpoint inhibitor; and   (ii) at least one agent which inhibits the Hedgehog (Hh) signalling pathway.   
     
     
         85 - 89 . (canceled)