Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy

Abstract

Disclosed herein are methods for treating cancer comprising administering at least one immune checkpoint inhibitor and at least one Retinoic Acid Receptor or Retinoid X Receptor active agent.

What is claimed is: 
     
         1 . A method of treating cancer comprising administering at least one immune checkpoint inhibitor, wherein the immune checkpoint inhibitor comprises an antibody specific for at least one of CTLA-4, PD-1, TIM-3, LAG-3, PD-L1, B7-H3, B7-H4, BTLA, ICOS, or OX40, and one or more means for potentiating activity of the immune checkpoint inhibitor to promote a T cell mediated immune response and wherein said means comprise a Retinoic Acid Receptor (RAR)¥ selective agonist. 
     
     
         2 . The method of  claim 1 , wherein said one or more means further comprise a RARα selective antagonist or a Retinoic X Receptor (RXR) antagonist. 
     
     
         3 . The method of  claim 1 , wherein the RAR¥ agonist is not: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the RAR¥ selective agonist is not CD437, CD2325, CD666, LY2813631, AGN 204647, or BMS961. 
     
     
         5 . The method of  claim 1 , wherein the RAR¥ selective agonist is not a compound of general formula (IV) 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently H or C 1-6  alkyl; R 3  is H or F; and X is O, S, CH 2 , C(R 4 ) 2 , or NR 5 , wherein R 4  and R 5  are independently H or C 1-6  alkyl. 
       
     
     
         6 . The method of  claim 2 , wherein the RARα antagonist is:
 a. a compound of general formula (I) 
 
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , R 3 , and R 6  are independently H or C 1-6  alkyl; R 4  and R 5  are independently H or F; Ar is phenyl, pyridyl, thienyl, furyl, or naphthyl; X is C(CH 3 ) 2 , O, S, or NR 7 , wherein R 7  is H or C 1-6  alkyl; X 1  is H or halogen such as F, Cl or Br; and R 8  is H or OH; 
         
         b. a compound of general formula (II) 
       
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  are independently C 1-6  alkyl; X is O, S, or CH 2 ; Y is O, S, CH 2 , or NR 3 , wherein R 3  is C 1-6  alkyl; Z is Cl or Br; W is H or OH; and U is independently H or F; 
         
         c. a compound of general formula (III) 
       
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  are independently H or C 1-6  alkyl; R 3  is H or F; Ar is phenyl, pyridyl, thienyl, furyl, or naphthyl; X is O, S, N, or CH 2 ; W is H or OH; and Z is Cl or Br; or 
         
         d. a compound having the structure of: 
       
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 2 , wherein the RXR antagonist is AGN195393, LGN100849, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the method comprises additionally administering at least one cancer chemotherapy agent. 
     
     
         9 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for PD-1. 
     
     
         10 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for PD-1. 
     
     
         11 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for CTLA-4. 
     
     
         12 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for ICOS. 
     
     
         13 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for OX40. 
     
     
         14 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for TIM-3. 
     
     
         15 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for LAG-3. 
     
     
         16 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for B7-H3. 
     
     
         17 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for B7-H4. 
     
     
         18 . The method of  claim 1 , wherein the wherein the immune checkpoint inhibitor comprises an antibody specific for BTLA.