Methods for treating cancer or modulating T cells or NK cells in a subject with cancer by administering cells comprising chimeric cytokine receptors

1. A method for treating a subject for cancer, which comprises the step of administering a pharmaceutical composition to a subject in need of treatment for the cancer,

said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR) and a chimeric antigen receptor (CAR),

(A) wherein said chimeric cytokine receptor comprises a first and a second chimeric transmembrane polypeptide, wherein:

(i) the first chimeric transmembrane polypeptide comprises:

(a) a first exodomain which comprises an antigen-binding domain of an antibody which binds a first epitope of a ligand;

(b) a first transmembrane domain; and

(c) a first cytokine receptor endodomain; and

(ii) the second chimeric transmembrane polypeptide comprises:

(a) a second exodomain which comprises an antigen-binding domain of an antibody which binds a second epitope of the ligand;

(b) a second transmembrane domain; and

(c) a second cytokine receptor endodomain;

wherein the ligand is a tumour secreted factor; and

wherein the first cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain; and wherein the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor; and

(B) wherein the CAR comprises an antigen-binding domain, a spacer domain, a transmembrane domain, and an endodomain, wherein the antigen-binding domain specifically binds a tumour-associated antigen (TAA).

2. A method according to claim 1 , which comprises the following steps:

(i) isolation of a cell-containing sample from a subject;

(ii) transduction or transfection of T cells or NK cells from the sample with: (a) a nucleic acid construct or (b) a vector comprising the nucleic acid construct; said nucleic acid construct comprising a sequence encoding the CCR and a sequence encoding the CAR; and

(iii) formulating the cells from (ii) to make the pharmaceutical composition.

3. A method for treating a subject for cancer, which comprises the step of administering a pharmaceutical composition to a subject in need of treatment for cancer, said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR) and a chimeric antigen receptor (CAR),

(A) wherein said CCR comprises a first and a second chimeric transmembrane polypeptide, wherein:

(i) the first chimeric transmembrane polypeptide comprises:

(a) a first exodomain which comprises a heavy chain variable domain (V H ) of an antibody that binds to the ligand;

(b) a first transmembrane domain; and

(c) a first cytokine receptor endodomain; and

(ii) the second chimeric transmembrane polypeptide comprises:

(a) a second exodomain which comprises a light chain variable domain (V L ) of the antibody that binds to the ligand;

(b) a second transmembrane domain; and

(c) a second cytokine-receptor endodomain;

wherein the ligand is a tumour secreted factor; and

wherein one of the first cytokine receptor endodomain and the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain; and wherein the other of the first cytokine receptor endodomain and the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor; and

(B) wherein the CAR comprises an antigen-binding domain, a spacer domain, a transmembrane domain, and an endodomain, wherein the antigen-binding domain specifically binds a tumour-associated antigen (TAA).

4. A method according to claim 3 , which comprises the following steps:

(i) isolation of a cell-containing sample from a subject;

(ii) transduction or transfection of T cells or NK cells from the sample with: (a) a nucleic acid construct or (b) a vector comprising the nucleic acid construct; said nucleic acid construct comprising a sequence encoding the CCR and a sequence encoding the CAR; and

(iii) formulating the cells from (ii) to make the pharmaceutical composition.

5. The method according to claim 4 , wherein the antigen-binding domains of the first exodomain of the CCR and the second exodomain of the CCR each comprises a single-chain variable fragment (scFv) that binds to the ligand.

6. The method according to claim 5 ,

wherein the first chimeric transmembrane polypeptide further comprises a first spacer connecting the first exodomain and the first transmembrane domain; and

wherein the second chimeric transmembrane polypeptide further comprises a second spacer connecting the second exodomain and the second transmembrane domain.

7. The method according to claim 6 , wherein the first spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk; and wherein the second spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk.

8. The method according to claim 5 , wherein the tumour secreted factor is selected from: prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), and CA125.

9. The method according to claim 5 , wherein the cancer is prostate cancer, and the tumour secreted factor comprises PSA.

10. The method according to claim 9 , wherein the tumour-associated antigen (TAA) comprises PSMA.

11. The method according to claim 3 ,

wherein the first chimeric transmembrane polypeptide further comprises a first spacer connecting the first exodomain and the first transmembrane domain; and

wherein the second chimeric transmembrane polypeptide further comprises a second spacer connecting the second exodomain and the second transmembrane domain.

12. The method according to claim 11 , wherein the first spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk; and wherein the second spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk.

13. The method according to claim 3 , wherein the tumour secreted factor is selected from: prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), and CA125.

14. The method according to claim 3 , wherein the cancer is prostate cancer, and the tumour secreted factor comprises PSA.

15. The method according to claim 14 , wherein the tumour-associated antigen (TAA) comprises PSMA.

16. A method of modulating a T cell or NK cell response in a subject with cancer, the method comprising the step of administering a pharmaceutical composition to a subject,

said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR), said chimeric cytokine receptor comprising a first and a second chimeric transmembrane polypeptide, wherein:

(i) the first chimeric transmembrane polypeptide comprises:

(a) a first exodomain which comprises an antigen-binding domain of an antibody which binds a first epitope of a ligand;

(b) a first transmembrane domain; and

(c) a first cytokine receptor endodomain; and

(ii) the second chimeric transmembrane polypeptide comprises:

(a) a second exodomain which comprises an antigen-binding domain of an antibody which binds a second epitope of the ligand;

(b) a second transmembrane domain; and

(c) a second cytokine receptor endodomain;

wherein the ligand is a tumour secreted factor; and

wherein one of the first cytokine receptor endodomain and the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain; and wherein the other of the first cytokine receptor endodomain and the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor.

17. The method according to claim 16 , wherein the antigen-binding domains of the first exodomain of the CCR and the second exodomain of the CCR each comprises a single-chain variable fragment (scFv) that binds to the ligand.

18. The method according to claim 17 ,

wherein the first chimeric transmembrane polypeptide further comprises a first spacer connecting the first exodomain and the first transmembrane domain; and

wherein the second chimeric transmembrane polypeptide further comprises a second spacer connecting the second exodomain and the second transmembrane domain.

19. The method according to claim 18 , wherein the first spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk; and wherein the second spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk.

20. The method according to claim 16 , wherein one of the first cytokine receptor endodomain and second cytokine receptor endodomain comprises an IL-2 receptor β-chain endodomain.

21. The method according to claim 16 , wherein one of the first cytokine receptor endodomain and second cytokine receptor endodomain comprises an IL-7 receptor α-chain endodomain.

22. A method of modulating a T cell or NK cell response in a subject with cancer, the method comprising the step of administering a pharmaceutical composition to a subject, said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR), said CCR comprising a first and a second chimeric transmembrane polypeptide, wherein:

(i) the first chimeric transmembrane polypeptide comprises:

(a) a first exodomain which comprises a heavy chain variable domain (V H ) of an antibody that binds to the ligand;

(b) a first transmembrane domain; and

(c) a first cytokine receptor endodomain; and

(ii) the second chimeric transmembrane polypeptide comprises:

(a) a second exodomain which comprises a light chain variable domain (V L ) of the antibody that binds to the ligand;

(b) a second transmembrane domain; and

(c) a second cytokine-receptor endodomain;

wherein the ligand is a tumour secreted factor; and

wherein one of the first cytokine receptor endodomain and the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain; and wherein the other of the first cytokine receptor endodomain and the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor.

23. The method according to claim 22 ,

wherein the first chimeric transmembrane polypeptide further comprises a first spacer connecting the first exodomain and the first transmembrane domain; and

wherein the second chimeric transmembrane polypeptide further comprises a second spacer connecting the second exodomain and the second transmembrane domain.

24. The method according to claim 23 , wherein the first spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk; and wherein the second spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk.

25. The method according to claim 22 , wherein the tumour secreted factor is selected from: prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), and CA125.

26. The method according to claim 22 , wherein one of the first cytokine receptor endodomain and second cytokine receptor endodomain comprises an IL-2 receptor β-chain endodomain.

27. The method according to claim 22 , wherein one of the first cytokine receptor endodomain and second cytokine receptor endodomain comprises an IL-7 receptor α-chain endodomain.