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, an
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.
대표청구항▼
1. A method of producing one or more compositions comprising human T cells which express a chimeric antigen receptor (CAR), wherein said human T cells are derived from primary human T cells and wherein said method comprises: (i) obtaining one or more compositions comprising isolated primary human T
1. A method of producing one or more compositions comprising human T cells which express a chimeric antigen receptor (CAR), wherein said human T cells are derived from primary human T cells and wherein said method comprises: (i) obtaining one or more compositions comprising isolated primary human T cells, each of said compositions being comprised of primary human T cells isolated from at least one human donor;(ii) modifying the primary human T cells comprised in said one or more compositions comprising primary human T cells in order to functionally impair or reduce expression of one or more components of the TCR complex endogenously expressed by said human primary T cells;(iii) further modifying the primary human T cells in the one or more compositions comprising human T cells by introducing a nucleic acid which encodes a desired CAR polypeptide which comprises a non-TCR receptor which comprises (1) a ligand binding domain which binds to an antigen expressed by cancer cells and (2) a signaling domain; thereby producing one or more compositions comprising human T cells which express at least one CAR that specifically binds to cancer cells. 2. The method of claim 1, wherein reduced expression of the targeted TCR component or the functional impairment or reduced expression of the endogenous TCR by the T cells in said one or more compositions obtained after effecting steps (i)-(iii) is confirmed by effecting one or more of the following procedures: (a) detecting the level of expression of said targeted TCR component in T cells comprised in said one or more compositions, (b) detecting the proliferation of T cells obtained in said one or more compositions in the presence of HLA-mismatched PMBCs and (c) detecting the level of gamma interferon produced by T cells comprised in said one or more compositions in response to HLA-mismatched donor cells. 3. The method of claim 1 wherein said one or more compositions comprising human T cells which express a CAR are derived from different human donors. 4. The method of claim 1 wherein said one or more compositions human T cells which express a CAR are derived from the same human donor. 5. The method of claim 1 wherein said one or more components of the TCR complex include TCR-α, TCR-β, TCR-γ, TCR-δ, CD3-γ, CD3-δ, CD3-ϵ, and CD3-ζ. 6. The method of claim 1 wherein in step (i) the functional impairment or reduced expression of the one or more components of the TCR complex is effected by introducing into the primary human T cells at least one short hairpin RNA (shRNA) which targets a nucleic acid that encodes at least one component of a functional TCR expressed by said primary human T cells. 7. The method of claim 6 wherein said one or more components of the TCR complex include TCR-α, TCR-β, TCR-γ, TCR-δ, CD3-γ, CD3-δ, CD3-ϵ, and CD3-ζ. 8. The method of claim 1 wherein the compositions are in a form whereby they may be stored and can be used for future therapy. 9. The method of claim 6 wherein the compositions are in a form whereby they may be stored and can be used for future therapy. 10. The method of claim 1, wherein the primary human T cells express CD4 or CD8. 11. The method of claim 6, wherein the primary human T cells express CD4 or CD8. 12. The method of claim 1, wherein the primary human T cells of (i) comprise human peripheral blood mononuclear cells or cytotoxic T cells. 13. The method of claim 6, wherein the primary human T cells of (i) comprise human peripheral blood mononuclear cells or cytotoxic T cells. 14. The method of claim 1, wherein the ligand binding domain in the CAR is obtained from NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26 or NKRP1. 15. The method of claim 1, wherein the ligand binding domain in the CAR is obtained from an anti-tumor chimeric antigen receptor or anti-tumor antibody. 16. The method of claim 1, wherein the signaling domain in the CAR is obtained from CD3 ζ. 17. The method of claim 1, wherein the chimeric receptor binds to (i) MIC-A, MIC-B, an estrogen receptor, a progesterone receptor, RON or one or more members of the ULBP family. 18. The method of claim 17, wherein the one or more members of the ULBP family include Rae-1, H-60, HCMV UL18, Rae-1β, ULBP2, and ULBP3. 19. The method of claim 1, further comprising engineering the primary human T cells to express another receptor which initiates a signal to T cells. 20. The method of claim 1, wherein the chimeric receptor comprises a ligand binding domain from NKG2D and a signaling domain from CD3 ζ. 21. The method of claim 1, wherein the chimeric receptor is chNKG2D. 22. The method of claim 6, wherein the ligand binding domain is a NKG2D ligand binding domain and the signaling domain is a CD3 ζ signaling domain.
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