T cell receptor-deficient T cell compositions
The invention is directed to modified T cells, methods of making and using isolated, modified T cells, and methods of using these isolated, modified T cells to address diseases and disorders. In one embodiment, this invention broadly relates to TCR-deficient T cells, isolated populations thereof, and compositions comprising the same. In another embodiment of the invention, these TCR-deficient T cells are designed to express a functional non-TCR receptor. The invention also pertains to methods of making said TCR-deficient T cells, and methods of reducing or ameliorating, or preventing or treating, diseases and disorders using said TCR-deficient T cells, populations thereof, or compositions comprising the same.
1. An isolated TCR-deficient T cell that does not express a functional TCR, wherein said T cell further expresses at least one functional exogenous non-TCR receptor which comprises a chimeric receptor comprising a ligand binding domain attached to a signaling domain.
2. The isolated TCR-deficient T cell of claim 1 , wherein said T cell lacks cell-surface expression of at least one component of the T cell receptor complex, as determined by flow cytometry.
3. The isolated TCR-deficient T cell of claim 1 , wherein said T cell lacks cell surface expression of all components of the T cell receptor complex, as determined by flow cytometry.
4. The isolated TCR-deficient T cell of claim 1 , wherein the ligand binding domain is obtained from NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, NKRP1, NKp30, NKp44, NKp46, CD244 (2B4), DNAM-1, or NKp80.
5. The isolated TCR-deficient T cell of claim 1 , wherein the ligand binding domain is obtained from an anti-tumor chimeric antigen receptor or anti-tumor antibody.
6. The isolated TCR-deficient T cell of claim 1 , wherein the signaling domain is obtained from CD3zeta, Dap10, CD28, 41BB, or CD40L.
7. The isolated TCR-deficient T cell of claim 1 , wherein the ligand binding domain binds MIC-A, MIC-B, Her2neu, EGFR, mesothelin, CD38, CD20, CD19, PSA, MUC1, MUC2, MUC3A, MUC3B, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, MUC20, estrogen receptor, progesterone receptor, RON, or one or more members of the ULBP/RAET1 family.
8. The isolated T cell of claim 7 , wherein the one or more members of the ULBP/RAET1 family is selected from ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, and ULBP6.
9. The isolated TCR-deficient T cell of claim 1 , wherein the ligand binding domain binds to virus antigen or viral-induced antigen found on the surface of an infected cell.
10. The isolated TCR-deficient T cell of claim 9 , wherein the virus is selected from HCMV, HIV, EBV, HBV, HCV, Ebola virus, a hantavirus, or VSV.
11. The isolated TCR-deficient T cell of claim 1 which is human.
12. The isolated TCR-deficient T cell of claim 1 which comprises a gene that encodes a dominant selectable marker.
13. A composition comprising an isolated TCR-deficient T cell of claim 1 .
14. The composition of claim 13 , comprising a pharmaceutically acceptable carrier.
15. The isolated TCR-deficient T cell of claim 1 , wherein the ligand binding domain is a NKG2D ligand binding domain, and the signaling domain is a CD3ζ signaling domain.