Methods and compositions for modifying the immune response

Abstract

The present invention is directed to methods and compositions for modulating proteins involved in the immune response. The present invention further provides methods and compositions for treatment of autoimmune disease and cancer by modulating the expression and activity of such proteins.

1 . A method for the treatment of cancer, the method comprising administering to a subject in need thereof a combination of a pharmaceutically effective amount of (i) at least one immune checkpoint inhibitor and (ii) an inhibitor of Toso activity. 
     
     
         2 . The method of  claim 1 , wherein the at least one immune checkpoint inhibitor is a member selected from the group consisting of: a PD-1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, and a TIM3 inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the inhibitor of Toso activity is a soluble Toso protein. 
     
     
         4 . The method of  claim 1 , wherein the inhibitor of Toso activity is an antibody to Toso. 
     
     
         5 . The method of  claim 1 , wherein the combination comprises a PD-1 inhibitor, a CTLA-4 inhibitor, and a soluble Toso protein. 
     
     
         6 . The method of  claim 5 , wherein the PD-1 inhibitor is an anti-PD-1 antibody and the CTLA-4 inhibitor is an anti-CTLA-4 antibody. 
     
     
         7 . A method for increasing a level of infiltrating lymphocytes in a tumor, the method comprising treating the tumor with a soluble Toso protein, wherein the level of infiltrating lymphocytes that results from the treating is higher than the level without the treating. 
     
     
         8 . The method of  claim 7 , wherein the infiltrating lymphocytes comprise CD3+ cells, CD8+ cells, or a combination of CD3+ cells and CD8+ cells. 
     
     
         9 . The method of  claim 7 , wherein the method further comprises treating the tumor with one or more of a member selected from a PD-1 inhibitor, a CTLA-4 inhibitor, and a PDL-1 inhibitor. 
     
     
         10 . A method of dampening the immune response, said method comprising decreasing expression and/or activity of Toso. 
     
     
         11 . A method according to  claim 10 , said method further comprising increasing expression and/or activity of IgM. 
     
     
         12 . A method according to  claim 10 , said method further comprising decreasing expression and/or activity of PAMPs and/or DAMPs. 
     
     
         13 . A method of treating autoimmune disease, said method comprising one or more of the following steps:
 (a) decreasing the expression and/or activity of Toso;   (b) increasing the expression and/or activity of IgM; and   (c) decreasing the expression and/or activity of PAMPs and/or DAMPs.   
     
     
         14 . A method of inducing the immune response, said method comprising increasing expression and/or activity of Toso. 
     
     
         15 . A method according to  claim 14 , said method further comprising decreasing expression and/or activity of IgM. 
     
     
         16 . A method according to  claim 14 , said method further comprising increasing expression and/or activity of PAMPs and/or DAMPs. 
     
     
         17 . A method according to  claim 14 , said method further comprising modulating activity of a scramblase protein. 
     
     
         18 . A method of treating cancer, said method comprising one or more of the following steps:
 (a) increasing the expression and/or activity of Toso;   (b) decreasing the expression and/or activity of IgM;   (c) increasing the expression and/or activity of PAMPs and/or DAMPs;   (d) modulating the activity of a scramblase protein.