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 the administration of a pharmaceutically effective amount of isolated primary human T cells or progeny thereof,
which isolated primary human T cells or progeny thereof:
(i) has been modified to functionally impair and/or to reduce expression of the endogenous T cell receptor (TCR), and
(ii) has been further modified to express at least one functional exogenous non-TCR chimeric receptor comprising (i) a ligand binding domain which binds to a ligand expressed by tumor cells of the treated subject and (ii) a signaling domain.
2. The method of claim 1 , wherein the treated human subject is histoincompatible (non-HLA matched) compared to the HLA allotype of the administered isolated modified primary human T cells or progeny thereof.
3. The method of human therapy of claim 1 , wherein the expression of the endogenous TCR is reduced in the administered isolated modified primary human T cells or progeny thereof.
4. The method of human therapy of claim 1 , wherein the functionality of the endogenous TCR is impaired in the administered isolated modified primary human T cells or progeny thereof.
5. The method of human therapy of claim 3 , 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.
6. The method of human therapy of claim 4 , 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.
7. The method of human therapy 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.
8. The method of human therapy 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.
9. The method of human therapy of claim 4 , 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 human therapy of claim 1 , wherein the chimeric receptor expressed by the isolated modified primary human T cells or progeny thereof comprises a NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, or NKRP1 polypeptide.
11. The method of human therapy of claim 2 , wherein the chimeric receptor expressed by the isolated modified primary human T cells or progeny thereof comprises a NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, or NKRP1 polypeptide.
12. The method of human therapy of claim 1 , wherein the chimeric receptor expressed by the isolated modified primary human T cells or progeny thereof comprises a chimeric Fv.
13. The method of treating cancer of claim 1 , wherein the ligand binding domain of the chimeric receptor is obtained from an anti-tumor chimeric antigen receptor or anti-tumor antibody.
14. The method of human therapy of claim 1 , wherein the non-TCR chimeric receptor expressed by the isolated modified primary human T cells or progeny thereof comprises a receptor that binds to MIC-A, MIC-B, estrogen, progesterone, RON, or one or more members of the ULBP/RAET1 family.
15. The method of human therapy of claim 14 , wherein the one or more members of the ULBP/RAET1 family is/are selected from the group consisting of ULBP2, ULBP3, Rae-1, H-60, HCMV UL18, or Rae-1β.
16. The method of human therapy of claim 1 , wherein the chimeric receptor comprises a NKG2D ligand binding domain and a CD3ζ signaling domain.
17. The method of human therapy of claim 1 , wherein the administered isolated modified primary human T cells or progeny thereof are derived from a T cell or primary human PBMCs of a human subject who is allogeneic relative to the treated human subject.
18. The method of human therapy of claim 1 , wherein the administered isolated modified primary human T cells or progeny thereof express CD4.
19. The method of human therapy of claim 1 , wherein the administered isolated modified primary human T cells or progeny thereof express CD8.
20. The method of human therapy of claim 1 , wherein the administered isolated modified primary human T cells or progeny thereof are capable of differentiating into T regulatory cells.