T CELL RECEPTOR-DEFICIENT T CELL COMPOSITIONS

• US 20120321667A1
• Filed: 10/29/2010
• Published: 12/20/2012
• Est. Priority Date: 10/29/2009
• Status: Active Grant

• Current Assignee: The Trustees of Dartmounth College (Dartmouth College)
• Original Assignee: The Trustees of Dartmounth College (Dartmouth College)
• Inventors: Sentman, Charles L.
• Granted Patent: US 9,181,527 B2
• Time in Patent Office: Days
• US Class Current: 424/278.1
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/48 Blood cells, e.g. leukemia or lymphoma
• CPC Class Codes: A61K 2239/59 Reproductive system, e.g. uterus, ovaries, cervix or testes
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4632 T-cell receptors [TCR]; antibody T-cell receptor constructs
• CPC Class Codes: A61K 39/464429 Molecules with a "CD" designation not provided for elsewhere
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C12N 2501/515 CD3, T-cell receptor complex
• CPC Class Codes: C12N 2510/02 Cells for production
• CPC Class Codes: C12N 2511/00 Cells for large scale production
• CPC Class Codes: C12N 5/0636 T lymphocytes
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

1. An isolated TCR-deficient T cell.

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.

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.

4. The isolated TCR-deficient T cell of claim 1, wherein said T cell does not express a functional TCR.

5. The isolated TCR-deficient T cell of claim 4, wherein said T cell further expresses at least one functional non-TCR receptor.

6. The isolated TCR-deficient T cell of claim 5, wherein the at least one functional non-TCR receptor is a chimeric receptor comprising a ligand binding domain attached to a signaling domain.

7. The isolated TCR-deficient T cell of claim 6, 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.

8. The isolated TCR-deficient T cell of claim 6, wherein the ligand binding domain is obtained from an anti-tumor chimeric antigen receptor or anti-tumor antibody.

9. The isolated TCR-deficient T cell of claim 8, wherein the anti-tumor antibody is obtained from an anti-Her2neu antibody or an anti-EGFR antibody.

10. The isolated TCR-deficient T cell of claim 6, wherein the signaling domain is obtained from CD3zeta, Dap10, CD28, 41BB, or CD40L.

11. The isolated TCR-deficient T cell of claim 5, wherein the at least one functional non-TCR receptor 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.

12. The isolated T cell of claim 11, wherein the one or more members of the ULBP/RAET1 family include ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, and ULBP6.

13. The isolated TCR-deficient T cell of claim 5, wherein the at least one functional non-TCR receptor binds to virus antigen or viral-induced antigen found on the surface of an infected cell.

14. The isolated TCR-deficient T cell of claim 13, wherein the virus is selected from HCMV, HIV, EBV, HBV, HCV, Ebola virus, a hantavirus, or VSV.

15. The isolated TCR-deficient T cell of claim 1 which is human.

16. The isolated TCR-deficient T cell of claim 1 which comprises a gene that encodes a dominant selectable marker.

17. A composition comprising an isolated TCR-deficient T cell of claim 1.

18. The composition of claim 17, comprising a therapeutically-effective amount of said isolated TCR-deficient T cells.

19. The composition of claim 17, comprising a pharmaceutical carrier.

20. A method of preventing or treating cancer, graft versus host disease, infection, one or more autoimmune disorders, transplantation rejection, or radiation sickness in an individual in need thereof, comprising administering the composition of claim 18 to said individual.

26. A method of preventing or treating cancer, graft versus host disease, infection, one or more autoimmune disorders, transplantation rejection, or radiation sickness in an individual in need thereof, comprising administering a therapeutically-effective amount of the isolated TCR-deficient T cells of claim 5 to said individual.

21-25. -25. (canceled)

27-31. -31. (canceled)

32. A T cell bank comprising TCR-deficient T cells of different tissue HLA types, wherein said T cell bank comprises different T cell containing compositions each composition containing T cells of a specific HLA type, which are TCR-deficient.

33. The T cell bank of claim 32 which comprises T cells of at least 10 different HLA tissue types.

34. The T cell bank of claim 32 which comprises T cells of from about 50-100 different HLA tissue types.

35. The T cell bank of claim 32 which contains T cells that are engineered to stably lack cell-surface expression of at least one component of the T cell receptor complex.