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. A method of treating cancer in a human subject in need thereof which comprises administering a pharmaceutically effective amount of isolated primary human T cells or progeny thereof, which isolated primary human T cells:
(i) have been modified to functionally impair and/or to reduce expression of the endogenous T cell receptor (TCR); and
(ii) have been modified to express at least one functional exogenous non-TCR receptor comprising a ligand binding domain which binds to a ligand expressed by tumor cells of said subject, which exogenous ligand binding domain directly or indirectly mediates T cell signaling upon the binding of the ligand binding domain to a ligand expressed by a tumor cell in the treated subject.
2. The method of treating cancer of claim 1 , wherein a pool of said isolated modified human T cells or progeny thereof is administered to the subject.
3. The method of treating cancer of claim 1 , wherein the cell comprises an exogenous signaling domain which initiates T cell signaling.
4. The method of treating cancer of claim 1 , wherein the ligand binding domain which binds to a ligand expressed by tumor cells is an anti-tumor antigen receptor or an anti-tumor antibody.
5. The method of treating cancer of claim 1 , wherein the expression of the endogenous TCR is reduced in the administered isolated modified primary human T cells or progeny thereof.
6. The method of treating cancer of claim 1 , wherein the functionality of the endogenous TCR is impaired in the administered isolated modified primary human T cells or progeny thereof.
7. The method of treating cancer of claim 1 , wherein the administered isolated modified primary human T cells or progeny thereof elicit a reduced graft versus host disease (GVHD) response against allogeneic (HLA-mismatched) cells in a treated subject compared to that elicited by isolated primary human T cells which express the same endogenous TCR but which endogenous TCR is not impaired.
8. The method of treating cancer of claim 1 , wherein the administered isolated modified primary human T cells or progeny thereof do not elicit a GVHD response in a histoincompatible human recipient.
9. The method of treating cancer of claim 3 , wherein the administered isolated modified primary human T cells or progeny thereof do not elicit a GVHD response in a histoincompatible human recipient.
10. The method of treating cancer of claim 1 , wherein the non-TCR receptor expressed by the isolated primary human T cells which binds to a ligand expressed by tumor cells comprises a NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, or NKRP1 polypeptide.
11. The method of treating cancer of claim 1 , wherein the non-TCR receptor expressed by the isolated primary human T cells which binds to a ligand expressed by tumor cells comprises a chimeric Fv.
12. The method of treating cancer of claim 1 , wherein the non-TCR receptor is a chimeric receptor which comprises (1) said ligand binding domain which binds to a ligand expressed by a ligand expressed by tumor cells of the treated subject and further comprises (2) a signaling domain.
13. The method of treating cancer of claim 12 , wherein the ligand binding domain of the chimeric receptor binds to a receptor selected from MIC-A, MIC-B, estrogen, progesterone, RON, or one or more members of the ULBP/RAET1 family.
14. The method of treating cancer of claim 12 , wherein the receptor ligand binding domain comprised in said chimeric receptor comprises a NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, or NKRP1 polypeptide.
15. The method of treating cancer of claim 1 , wherein the ligand binding domain which binds to a ligand expressed by tumor cells comprises an NKG2D polypeptide.
16. The method of treating cancer of claim 1 , wherein the ligand binding domain which binds to a ligand expressed by tumor cells comprises a natural killer (NK) cell receptor.
17. The method of treating cancer of claim 1 , wherein the non-TCR receptor is a chimeric receptor which comprises: (1) said ligand binding domain which binds to a ligand expressed by tumor cells of the treated subject; and (2) a signaling domain, wherein said ligand binding domain comprises a NKG2D ligand binding domain, and said signaling domain comprises a CD3ζ signaling domain.
18. The method of treating cancer of claim 1 , wherein the administered isolated primary human T cells or progeny thereof are derived from allogeneic T cells or primary human PBMCs of a human subject.
19. The method of treating cancer of claim 1 , wherein the administered isolated primary human T cells or progeny thereof express CD4.
20. The method of treating cancer of claim 1 , wherein the administered isolated primary human T cells or progeny thereof express CD8.
21. The method of treating cancer of claim 1 , wherein the administered isolated primary human T cells or progeny thereof are capable of differentiating into T regulatory cells.