T-cell receptor-deficient T cell compositions
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-005/10
A61K-035/17
C12N-005/0783
A61K-035/12
출원번호
US-0383717
(2016-12-19)
등록번호
US-9821011
(2017-11-21)
발명자
/ 주소
Sentman, Charles L.
출원인 / 주소
THE TRUSTEES OF DARTMOUTH COLLEGE
대리인 / 주소
Teskin, Robin L.
인용정보
피인용 횟수 :
0인용 특허 :
43
초록▼
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 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/o
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.
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