Methods for treating cancer or modulating T cells or NK cells in a subject by administering cells comprising chimeric transmembrane proteins
The present invention provides a chimeric cytokine receptor (CCR) comprising: (i) an exodomain which binds to a ligand selected from a tumour secreted factor, a chemokine and a cell-surface antigen; and (ii) a cytokine receptor endodomain.
1. A method for treating a subject for cancer, which comprises the step of administering a pharmaceutical composition to the subject, said pharmaceutical composition comprising a plurality of cells, said cells comprising a chimeric transmembrane protein and a chimeric antigen receptor (CAR),
(A) wherein said chimeric transmembrane protein comprises:
(i) a first polypeptide which comprises
(a) a first dimerization domain comprising the dimerization portion of an antibody heavy chain constant domain (C H ) and
(b) a first chain of a cytokine receptor endodomain; and
(ii) a second polypeptide which comprises
(a) a second dimerization domain comprising the dimerization portion of an antibody light chain constant domain (C L ), which dimerizes with the first dimerization domain and
(b) a second chain of the cytokine-receptor endodomain,
wherein one of the first and second chains of the cytokine receptor endodomain comprises 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 and second chains of the cytokine receptor endodomain comprises a γ-chain receptor endodomain that is common to the IL-2, IL-7, and IL-15 receptors; and
wherein the first and second polypeptides spontaneously dimerize; 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. The method according to claim 1 , which comprises:
(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 encoding the chimeric transmembrane protein and the CAR; and
(iii) formulating the cells from (ii) to make the pharmaceutical composition.
3. The method according to claim 1 , wherein:
(i) the first polypeptide comprises
(a) a heavy chain constant domain (C H ) and
(b) a first chain of the cytokine receptor endodomain; and
(ii) the second polypeptide comprises
(a) a light chain constant domain (C L ) and
(b) a second chain of the cytokine-receptor endodomain.
4. The method according to claim 3 , wherein the first polypeptide comprises an antibody heavy chain variable domain (V H ) and a heavy chain constant domain (C H ); and the second polypeptide comprises an antibody light chain variable domain (V L ) and a light chain constant domain (C L ).
5. The method according to claim 1 , wherein the TAA is PSMA.
6. The method according to claim 1 , wherein the TAA is GD2.
7. A method for modulating a T cell or NK cell response in a subject, the method comprising administering a pharmaceutical composition to the subject, said pharmaceutical composition comprising a plurality of T cells or NK cells, said cells comprising a chimeric transmembrane protein, said chimeric transmembrane protein comprising:
(i) a first polypeptide which comprises
(a) a first dimerization domain comprising the dimerization portion of an antibody heavy chain constant domain (C H ) and
(b) a first chain of a cytokine receptor endodomain; and
(ii) a second polypeptide which comprises
(a) a second dimerization domain comprising the dimerization portion of an antibody light chain constant domain (C L ), which dimerizes with the first dimerization domain and
(b) a second chain of the cytokine-receptor endodomain,
wherein one of the first and second chains of the cytokine receptor endodomain comprises 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 and second chains of the cytokine receptor endodomain comprises a γ-chain receptor endodomain that is common to the IL-2, IL-7, and IL-15 receptors; and
wherein the first and second polypeptides spontaneously dimerize.
8. The method according to claim 7 , wherein:
(i) the first polypeptide comprises
(a) a heavy chain constant domain (C H ) and
(b) a first chain of the cytokine receptor endodomain; and
(ii) the second polypeptide comprises
(a) a light chain constant domain (C L ) and
(b) a second chain of the cytokine-receptor endodomain.
9. The method according to claim 7 , wherein the first polypeptide comprises an antibody heavy chain variable domain (V H ) and a heavy chain constant domain (C H ); and the second polypeptide comprises an antibody light chain variable domain (V L ) and a light chain constant domain (C L ).
10. The method according to claim 9 , wherein one of the first and second chains of the cytokine receptor endodomain comprises an IL-2 receptor β-chain endodomain.
11. The method according to claim 9 , wherein one of the first and second chains of the cytokine receptor endodomain comprises an IL-7 receptor α-chain endodomain.