Inhibition of Diacylglycerol Kinase to Augment Adoptive T cell Transfer

Abstract

The present invention provides compositions and methods for inhibiting one or more diacylglycerol kinase (DGK) isoform in a cell in order to enhance the cytolytic activity of the cell. In one embodiment, the cells may be used in adoptive T cell transfer. For example, in some embodiments, the cell is modified to express a chimeric antigen receptor (CAR). Inhibition of DGK in T cells used in adoptive T cell transfer increases cytolytic activity of the T cells and thus may be used in the treatment of a variety of conditions, including cancer, infection, and immune disorders.

1 . A composition for enhancing the cytolytic activity of a T cell modified to express a chimeric antigen receptor (CAR), said composition comprising an inhibitor of diacylglycerol kinase (DGK), wherein the inhibitor utilizes CRISPR technology. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the T cell is an activated T cell. 
     
     
         5 . (canceled) 
     
     
         6 . The composition of  claim 1 , wherein the composition inhibits a DGK isoform selected from the group consisting of DGKα and DGKζ. 
     
     
         7 . The composition of  claim 1 , wherein the composition inhibits both DGKα and DGKζ. 
     
     
         8 . An isolated T cell having enhanced cytolytic activity, wherein the T cell is modified to express a chimeric antigen receptor (CAR), and wherein said T cell is engineered to lack at least one DGK isoform. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The cell of  claim 8 , wherein the T cell is an activated T cell. 
     
     
         12 . (canceled) 
     
     
         13 . The cell of  claim 8 , wherein the DGK isoform is selected from the group consisting of DGKα and DGKζ. 
     
     
         14 . The cell of  claim 8 , wherein the lack of at least one DGK isoform is achieved in the cell using CRISPR technology. 
     
     
         15 . A method of enhancing the cytolytic activity of a T cell, said method comprising engineering the cell to express a chimeric antigen receptor (CAR) and to lack at least one DGK isoform. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 15 , wherein the T cell is an activated T cell. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 15 , wherein the DGK isoform is selected from the group consisting of DGKα and DGKζ. 
     
     
         21 . The method of  claim 15 , wherein the DGK isoform is both DGKα and DGKζ. 
     
     
         22 . The method of  claim 15 , wherein CRISPR is used to engineer the cell to lack at least one DGK isoform. 
     
     
         23 . (canceled) 
     
     
         24 . A method of enhancing adoptive T cell transfer in a subject, said method comprising engineering a T cell to express a chimeric antigen receptor (CAR) and to lack at least one DGK isoform, wherein the T cell is administered to the subject during adoptive T cell transfer. 
     
     
         25 . (canceled) 
     
     
         26 . The method  claim 24 , wherein the T cell is an activated T cell. 
     
     
         27 . The method of  claim 24 , wherein the T cell is an autologous T cell. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 24 , wherein the the DGK isoform is selected from the group consisting of DGKα and DGKζ. 
     
     
         30 . The method of  claim 24 , wherein the DGK isoform is both DGKα and DGKζ. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled)