Inhibition of diacylglycerol kinase to augment adoptive T cell transfer
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 with enhanced cytolytic activity, said composition comprising an inhibitor of diacylglycerol kinase (DGK) or a downstream effector protein thereof and a T cell modified with a chimeric antigen receptor (CAR).
2. The composition of claim 1 , wherein the inhibitor is selected from the group consisting of a small interfering RNA (siRNA), short hairpin RNA (shRNA), an antisense nucleic acid, a ribozyme, a dominant negative mutant, an antibody, a peptide, a zinc finger nuclease, and a small molecule.
3. The composition of claim 1 , wherein the inhibitor enhances the T cell's effector activity.
4. The composition of claim 1 , wherein the inhibitor increases IFNγ secretion by the T cell.
5. The composition of claim 1 , wherein the composition inhibits the DGK isoform selected from the group consisting of DGKα and DGKζ.
6. The composition of claim 1 , wherein the composition inhibits both DGKα and DGKζ.
7. An isolated T cell with enhanced cytolytic activity, wherein the T cell comprises an inhibitor of DGK or a downstream effector protein thereof and a chimeric antigen receptor (CAR).
8. The cell of claim 7 , wherein the inhibitor is selected from the group consisting of a small interfering RNA (siRNA), short hairpin RNA (shRNA), an antisense nucleic acid, a ribozyme, a dominant negative mutant, an antibody, a peptide, a zinc finger nuclease, and a small molecule.
9. The cell of claim 7 , wherein the inhibitor enhances the T cell's effector activity.
10. The cell of claim 9 , wherein the inhibitor increases IFNγ secretion by the T cell.
11. The cell of claim 7 , wherein the composition inhibits the DGK isoform selected from the group consisting of DGKα and DGKζ.
12. The cell of claim 7 , wherein the cell comprises an inhibitor of DGKα and DGKζ.
13. The composition of claim 1 , wherein the T cell is a human T cell.
14. The cell of claim 7 , wherein the T cell is a human T cell.