DOSAGE REGIMEN FOR A COMBINATION THERAPY CONSISTING OFTCR-ENGINEERED T-CELLS IN COMBINATION WITH A PD-1 AXIS BINDING ANTAGONIST
The disclosure relates to a method of treating cancer, and to a population of modified T cells for use in a method of treating cancer.
1 . A method of treating cancer in an individual, comprising:
(a) administering to the individual a population of modified T cells comprising a heterologous CD8 co-receptor and a heterologous TCR capable of binding to MAGE-A4; and
(b) sustaining the function of (i) the population of modified T cells and/or (ii) endogenous T cells in the individual by administering an initial dose of a PD-1 axis binding antagonist to the individual about three weeks to about five weeks after step (a).
2 . A population of modified T cells for use in a method of treating cancer in an individual, wherein the modified T cells comprise a heterologous CD8 co-receptor and a heterologous TCR capable of binding to MAGE-A4, and the method comprises:
(a) administering the population to the individual; and
(b) sustaining the function of (i) the population of modified T cells and/or (ii) endogenous T cells in the individual by administering an initial dose of a PD-1 axis binding antagonist to the individual about three weeks to about five weeks after step (a).
3 . A PD-1 axis binding antagonist for use in a method of treating cancer in an individual, wherein the method comprises:
(a) administering to the individual a population of modified T cells comprising a heterologous CD8 co-receptor and a heterologous TCR capable of binding to MAGE-A4; and
(b) sustaining the function of (i) the population of modified T cells and/or (ii) endogenous T cells in the individual by administering an initial dose of the PD-1 axis binding antagonist to the individual about three weeks to about five weeks after step (a).
4 . The method of claim 1 , population for use of claim 2 , or PD-1 axis binding antagonist for use of claim 3 , wherein the initial dose of the PD-1 axis binding antagonist is administered to the individual about four weeks after administration of the population of modified T cells.
5 . The method of claim 1 or 4 , population for use of claim 2 or 4 , or PD-1 axis binding antagonist for use of claim 3 or 4 , wherein the method further comprises administering one or more further doses of the PD-1 axis binding antagonist, optionally wherein the one or more further doses are administered once every four weeks (Q4W) beginning four weeks from administration of the initial dose.
6 . The method of any one of claims 1, 4 and 5 , the population for use of any one of claims 2, 4 and 5 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 5 , wherein administration of the PD-1 axis binding antagonist reduces exhaustion (i) within the population of modified T cells and/or within T cells descended from the population of modified T cells, and/or (ii) within endogenous T cells in the individual.
7 . The method of any one of claims 1 and 4 to 6 , the population for use of any one of claims 2 and 4 to 6 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 6 , wherein the heterologous TCR binds to SEQ ID NO: 1.
8 . The method of any one of claims 1 and 4 to 7 , the population for use of any one of claims 2 and 4 to 7 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 7 , wherein the heterologous TCR comprises an alpha chain amino acid sequence having at least 80% sequence identity to SEQ ID NO: 2.
9 . The method of any one of claims 1 and 4 to 8 , the population for use of any one of claims 2 and 4 to 8 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 8 , wherein the heterologous TCR comprises a beta chain amino acid sequence having at least 80% sequence identity to SEQ ID NO: 3.
10 . The method of any one of claims 1 and 4 to 9 , the population for use of any one of claims 2 and 4 to 9 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 9 , wherein the CD8 co-receptor is CD8α.
11 . The method of any one of claims 1 and 4 to 10 , the population for use of any one of claims 2 and 4 to 10 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 10 , wherein the CD8 co-receptor comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10.
12 . The method of any one of claims 1 and 4 to 11 , the population for use of any one of claims 2 and 4 to 11 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 11 , wherein the modified T cells are autologous with respect to the individual.
13 . The method, population for use, or PD-1 axis binding antagonist for use of claim 12 , wherein the method comprises producing the population by:
(i) obtaining peripheral blood mononuclear cells (PBMCs) from the individual;
(ii) selecting T cells from the PBMCs; and
(iii) modifying the selected T cells to express a heterologous CD8 co-receptor and a heterologous TCR capable of binding to MAGE-A4.
14 . The method of any one of claims 1 and 4 to 13 , the population for use of any one of claims 2 and 4 to 13 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 13 , wherein the method comprises administering lymphodepleting chemotherapy to the individual prior to administration of the population of modified T cells.
15 . The method of any one of claims 1 and 4 to 14 , the population for use of any one of claims 2 and 4 to 14 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 14 , wherein the population comprises 0.8×10 9 to 10×10 9 modified T cells, optionally wherein the population comprises 0.8×10 9 to 1.2×10 9 modified T cells, 1.2×10 9 to 6×10 9 modified T cells, or 1.0×10 9 to 10×10 9 modified T cells.
16 . The method of any one of claims 1 and 4 to 15 , the population for use of any one of claims 2 and 4 to 15 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 15 , wherein the population comprises about 1.0×10 9 modified T cells, about 5.0×10 9 modified T cells, or about 10×10 9 modified T cells.
17 . The method of any one of claims 1 and 4 to 16 , the population for use of any one of claims 2 and 4 to 16 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 16 , wherein the population of modified T cells is administered as a single dose.
18 . The method of any one of claims 1 and 4 to 17 , the population for use of any one of claims 2 and 4 to 17 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 17 , wherein the population of modified T cells is administered intravenously.
19 . The method of any one of claims 1 and 4 to 18 , the population for use of any one of claims 2 and 4 to 18 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 18 , wherein the PD-1 axis binding antagonist is a PD1 binding antagonist.
20 . The method, population for use, or PD-1 axis binding antagonist for use of claim 19 , wherein the PD1 binding antagonist is an antibody that binds PD-1.
21 . The method, population for use, or PD-1 axis binding antagonist for use of claim 20 , wherein the antibody is nivolumab.
22 . The method of any one of claims 1 and 4 to 21 , the population for use of any one of claims 2 and 4 to 21 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 21 , wherein each dose of the PD-1 axis binding antagonist comprises 200 mg to 700 mg of the PD-1 axis binding antagonist.
23 . The method, population for use, or PD-1 axis binding antagonist for use of claim 22 , wherein each dose of the PD-1 axis binding antagonist comprises 300 mg to 600 mg, 400 mg to 500 mg, 450 mg to 500 mg, or 480 mg of the PD-1 axis binding antagonist.
24 . The method of any one of claims 1 and 4 to 23 , the population for use of any one of claims 2 and 4 to 23 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 23 , wherein each dose of the PD-1 axis binding antagonist comprises 480 mg of nivolumab.
25 . The method of any one of claims 1 and 4 to 24 , the population for use of any one of claims 2 and 4 to 24 , or the PD-1 axis binding antagonist for use of any one of claims 3 to 24 , wherein the cancer expresses MAGE-A4 and/or is a solid tumour, optionally wherein the solid tumour is urothelial cancer, head and neck cancer, non-small cell lung cancer (NSCLC), oesophageal caner, oesophogastric cancer, gastric cancer, ovarian cancer, melanoma, or endometrial cancer.