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 subject by administering a therapeutically effective amount of an isolated modified primary human T cell to a subject in need thereof, said therapeutically effective amount being one sufficient to kill cancer cells in the treated subject, wherein said isolated modified primary human T cell is derived from a primary human T cell isolated from a human donor, and (i) is modified to functionally impair or to reduce expression of the endogenous T cell receptor (TCR), and (ii) is further modified to express at least one functional exogenous non-TCR that comprises a chimeric receptor which recognizes a ligand expressed on the surface of cancer cells in the treated subject, said chimeric receptor comprising a ligand binding domain attached to a signaling domain, wherein the isolated primary human T cell modified as in (i) and (ii) elicits no or a reduced graft-versus-host disease (GVHD) response in a histoincompatible human recipient as compared to the GVHD response elicited by a primary human T cell isolated from the same human donor that is only modified as in (ii), and further wherein the isolated modified primary human T cell recognizes and kills cancer cells.
2. The method of claim 1 , wherein the chimeric receptor comprises a chimeric natural killer (NK) cell receptor.
3. The method of claim 1 , wherein the chimeric receptor comprises a NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, or NKRP1 polypeptide.
4. The method of claim 1 , wherein the ligand binding domain is obtained from an anti-tumor chimeric antigen receptor or an anti-tumor antibody.
5. The method of claim 1 , wherein the chimeric receptor comprises a receptor that hinds to MIC-A, MIC-B, estrogen, progesterone, RON, or one or more members of the ULBP/RAET1 family.
6. The method of claim 5 , wherein the one or more members of the ULBP/RAET1 family is/are selected from ULBP2, ULBP3, Rae-1, H-60, HCMV UL18, or Rae-1β.
7. The method of claim 1 , wherein the ligand binding domain is a NKG2D ligand binding domain and the signaling domain is a CD3 signaling domain.
8. The method of claim 1 , wherein the isolated modified primary human T cell is derived from an allogeneic T cell or primary human PBMCs isolated from a human subject.
9. The method of claim 1 , wherein the isolated modified primary human T cell expresses CD4 or CD8.
10. The method of claim 1 , wherein the isolated modified primary human T cell is capable of differentiating into a T regulatory cell.
11. The method of claim 1 , wherein the isolated modified primary human T cell is capable of producing effector molecules.
12. The method of claim 11 , wherein the effector molecules are interferon gamma (IFN-γ) and interleukin 2 (IL-2).
13. The method of claim 1 , wherein the reduced GVHD response is evidenced by the isolated primary human T cell modified as in (i) and (ii) eliciting reduced expression of gamma interferon as compared to a primary human T cell isolated from the same human donor that is only modified as in GO.
14. The method of claim 1 , wherein the reduced GVHD response is evidenced by the isolated primary human T cell modified as in (i) and (ii) not eliciting an increase in expression of gamma interferon as compared to a primary human T cell isolated from the same human donor that is only modified as in (ii).
15. The method of claim 1 , wherein the isolated primary human T cell modified as in (i) and (ii) does not elicit a GVHD response in a human recipient.