Engineered t cells with nk cell receptors & uses thereof
Patent Information
- Application Number
- HK62026127482
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-08-08
- Filing Date
- 2026-08-13
- Publication Date
- 2026-09-18
- Estimated Expiration
- 2044-08-07
Smart Images
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Abstract
Description
This document discloses compositions and methods for engineering T cells expressing DNAX helper molecule-1 (DNAM-1) peptide and / or NKG2D peptide, and methods for treating cancer. Abstract
Claims
Attorney Docket Number 11390-016WO1 CLAIMS What is claimed is:
1. A genetically modified T cell comprising one or more recombinant nucleic acid sequences encoding a natural killer (NK) cell receptor (NKR); wherein the NK cell receptor comprises a polypeptide of DNAX accessory molecule-1 (DNAM-1), NKG2D, NKp46, NKp30, NKp44, NKp80, 2B4, CD2, CD16 (FcγRIIIα), CD27, CD94 / NKG2C, SEMA4D, CRTAM, CD160, CD244, SLAMF6, SLAMF7, KLRD1, KLRD3, KLRC3, KLRC2, NCR1, NCR2, NCR3, KLRF1, FCGR3A, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DS1, TLR2, TLR3, TLR5, TLR7 / 8, or TLR9.
2. The genetically modified T cell of claim 1, wherein the NKR comprises DNAM-1 or NKG2D.
3. The genetically modified T cell of claim 1 or 2, comprising an increased level of the NKR relative to a reference control.
4. The genetically modified T cell of any one of claims 1-3, wherein the one or more recombinant nucleic acid sequences encoding the NKR comprise one or more point mutations.
5. The genetically modified T cell of any one of claims 1-4, further comprising one or more recombinant nucleic acid sequences encoding a chimeric antigen receptor (CAR) polypeptide or a transgenic T cell receptor (TCR) polypeptide.
6. The genetically modified T cell of any one of claims 1-5, wherein the CAR polypeptide comprises a single-chain variable fragment (scFV) that binds to a tumor antigen.
7. The genetically modified T cell of claim 6, wherein the scFV or the TCR polypeptide recognizes the tumor antigen.
8. The genetically modified T cell of claim 6 or 7, wherein the scFV or the TCR polypeptide are low affinity for the tumor antigen.Attorney Docket Number 11390-016WO1 9. The genetically modified T cell of any one of claims 1-8, wherein the recombinant nucleic acid sequences encoding the NKR, and the CAR polypeptides are operatively linked.
10. The genetically modified T cell of any one of claims 1-8, wherein the recombinant nucleic acid sequences encoding the NKR and the TCR polypeptide are operatively linked.
11. The genetically modified T cell of any one of claims 1-9, wherein the recombinant nucleic acid sequences encoding the NKR, and the CAR polypeptides are encoded on a vector, and wherein the nucleic acid sequences encoding the NKR, and the CAR are encoded on the same vector or different vectors.
12. The genetically modified T cell of any one of claim 1-8 and 10, wherein the recombinant nucleic acid sequences encoding the NKR and the TCR polypeptide are encoded on a vector, and wherein the nucleic acid sequences encoding the NKR and the TCR polypeptide are on the same vector or different vectors.
13. The genetically modified T cell of any one of claims 1-12, comprising a deletion of a CD28 gene or a fragment thereof.
14. The genetically modified T cell of any one of claims 1-13, wherein the T cell is a primary T cell, a T cell line, a tumor infiltrating lymphocyte, an effector T cell, a memory T cell, a TEMRA, or a stem cell-like memory T cell.
15. A method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of the genetically modified T cell of any one of claims 1-14.
16. The method of claim 15, wherein the subject has previously received a treatment comprising chemotherapy, radiotherapy, targeted therapy, biologic therapy, or combinations thereof.
17. The method of claims 15 or 16, wherein the treatment enhances levels of one or more ligands of the NKR on a cancer cell from the subject.Attorney Docket Number 11390-016WO1 18. The method of claim 17, wherein the NKR is DNAM-1; and wherein one or more ligands of DNAM-1 comprise Nectin-2 or poliovirus receptor (PVR).
19. The method of claim 17, wherein the NKR is NKG2D; and wherein the one or more ligands of NKG2D comprise ULBP1, ULBP2, ULBP3, H60, Rae-1α, Rae-1β, Rae-1δ, Rae-1γ, MICA, MICB, or HLA-A.
20. A method of treating cancer in a subject in need, comprising a) creating a genetically modified T cell comprising one or more recombinant nucleic acid sequences encoding a natural killer (NK) cell receptor (NKR); wherein the NK cell receptor comprises a polypeptide of DNAX accessory molecule-1 (DNAM-1), NKG2D, NKp46, NKp30, NKp44, NKp80, 2B4, CD2, CD16 (FcγRIIIα), CD27, CD94 / NKG2C, SEMA4D, CRTAM, CD160, CD244, SLAMF6, SLAMF7, KLRD1, KLRD3, KLRC3, KLRC2, NCR1, NCR2, NCR3, KLRF1, FCGR3A, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DS1, TLR2, TLR3, TLR5, TLR7 / 8, or TLR9; b) determining if the genetically modified T cell has a low affinity T cell receptor for a tumor antigen; and c) administering to the subject a therapeutically effective amount of the genetically modified T cell if the T cell has a low affinity T cell receptor for a tumor antigen.
21. The method of claim 20, wherein the one or more recombinant nucleic acid sequences encoding the NKR comprise one or more point mutations.
22. The method of claim 20 or 21, wherein the T cell comprises an increased level of DNAM-1 polypeptide, NKG2D polypeptide, and / or alternative NKR polypeptide relevant to a reference control.
23. The method of any one of claims 20-22, wherein the T cell comprises one or more recombinant nucleic acid sequences encoding a chimeric antigen receptor (CAR) polypeptide or a transgenic T cell receptor (TCR) polypeptide, wherein the CAR polypeptide comprises a single-chain variable fragment (scFV) that binds to a tumor antigen.Attorney Docket Number 11390-016WO1 24. The method of any one of claims 20-23, wherein the scFV or the TCR polypeptide recognizes the tumor antigen.
25. The method of any one of claims 20-24, wherein the scFV or the TCR polypeptide are low affinity for the tumor antigen.
26. The method of any one of claims 20-25, wherein the recombinant nucleic acid sequences encoding the NKR, and the CAR polypeptides are operatively linked.
27. The method of any one of claims 20-25, wherein the recombinant nucleic acid sequences encoding the NKR and the TCR polypeptides are operatively linked.
28. The method of any one of claims 20-26, wherein the recombinant nucleic acid sequences encoding the NKR, and the CAR polypeptides are encoded on a vector, and wherein the nucleic acid sequences encoding the NKR, and the CAR are encoded on the same vector or different vectors.
29. The method of any one of claims 20-25 and 27, wherein the recombinant nucleic acid sequences encoding the NKR and the TCR polypeptide are encoded on a vector, and wherein the nucleic acid sequences encoding the NKR and the TCR polypeptide are on the same vector or different vectors.
30. The method of any one of claims 20-29, wherein the T cell comprises a deletion of a CD28 gene or a fragment thereof.
31. The method of any one of claims 20-30, wherein the T cell is a primary T cell, a T cell line, a tumor infiltrating lymphocyte, an effector T cell, a memory T cell, a TEMRA, or a stem cell-like memory T cell.
32. The method of any one of claims 20-31, further comprising treating the subject with a treatment selected from chemotherapy, radiotherapy, targeted therapy, biologic therapy, or combinations thereof prior to administration of the T cells.Attorney Docket Number 11390-016WO1 33. The method of claim 32, wherein the treatment enhances levels of one or more ligands of the NKR on a cancer cell from the subject.
34. The method of claim 33, wherein the NKR is DNAM-1; and wherein one or more ligands of DNAM-1 comprise Nectin-2 or poliovirus receptor (PVR).
35. The method of claim 34, wherein the NKR is NKG2D; and wherein the one or more ligands of NKG2D comprise ULBP1, ULBP2, ULBP3, H60, Rae-1α, Rae-1β, Rae-1δ, Rae-1γ, MICA, MICB, or HLA-A.