MODIFIED T-CELLS FOR USE IN THE TREATMENT OF BLADDER CANCER
The disclosure relates to a method of treating bladder cancer, and to a population of modified immunoresponsive cells expressing a heterologous TCR for use in such method.
1 . A method of treating bladder cancer in an individual, comprising administering to the individual a population of modified T cells comprising a heterologous T-cell receptor (TCR) capable of binding to a peptide antigen of MAGE-A4.
2 . The method of claim 1 , wherein the method further comprises administering a checkpoint inhibitor to the individual, optionally wherein the population of modified T cells and the checkpoint inhibitor are administered in the same line of therapy.
3 . The method of claim 2 , wherein:
(a) administration of the checkpoint inhibitor begins before administration of the population of modified T cells, and continues after administration of the population of modified T cells; or
(b) administration of the checkpoint inhibitor begins at the same time as or after administration of the population of modified T cells, and continues after administration of the population of modified T cells.
4 . The method of claim 2 , wherein the checkpoint inhibitor comprises a Programmed Death-1 (PD-1) axis binding antagonist, optionally pembrolizumab.
5 . The method of claim 1 , wherein the method further comprises administering an additional anti-cancer therapy to the individual, optionally wherein:
(a) population of modified T cells and the additional anti-cancer therapy are administered in the same line of therapy; and/or
(b) the additional anti-cancer therapy is a chemotherapy.
6 . The method of claim 5 , wherein:
(a) administration of the additional anti-cancer therapy begins before administration of the population of modified T cells, and continues after administration of the population of modified T cells; or
(b) administration of the additional anti-cancer therapy begins at the same time as or after administration of the population of modified T cells, and continues after administration of the population of modified T cells.
7 . The method of claim 1 , wherein the bladder cancer is relapsed bladder cancer.
8 . The method of claim 7 , wherein the bladder cancer has relapsed following curative intent treatment for locally advanced bladder cancer, optionally wherein:
(a) the curative intent treatment comprises surgical resection and/or radiation therapy; and/or
(b) the curative intent treatment comprises systemic therapy.
9 . The method of claim 7 , wherein:
(a) the method comprises administering a checkpoint inhibitor to the individual and administration of the checkpoint inhibitor begins at the same time as or after administration of the population of modified T cells and continues after administration of the population of modified T cells; and/or
(b) the method comprises administering an additional anti-cancer therapy to the individual and administration of the additional anti-cancer therapy begins at the same time as or after administration of the population of modified T cells and continues after administration of the population of modified T cells, optionally wherein the additional anti-cancer therapy is a chemotherapy.
10 . The method of claim 1 , wherein the individual has not previously been treated for the bladder cancer, optionally wherein the bladder cancer is newly metastatic or unresectable locally advanced bladder cancer.
11 . The method of claim 10 , wherein:
(a) the method comprises administering a checkpoint inhibitor to the individual, and administration of the checkpoint inhibitor begins before or at the same time as administration of the population of modified T cells and continues after administration of the population of modified T cells; or
(b) the method comprises administering an additional anti-cancer therapy to the individual, and administration of the additional anti-cancer therapy begins before or at the same time as administration of the population of modified T cells and continues after administration of the population of modified T cells, optionally wherein the additional anti-cancer therapy is a chemotherapy.
12 . The method of claim 1 , wherein:
(a) the population of modified T cells is administered as soon as possible after diagnosis of the bladder cancer; and/or
(b) the population of modified T cells is administered as a single dose.
13 . The method of claim 1 , wherein:
(a) the heterologous TCR binds to GVYDGREHTV (SEQ ID NO: 1) in complex with an HLA molecule;
(b) the heterologous TCR comprises an alpha chain amino acid sequence having at least 80% sequence identity to SEQ ID NO: 2 and a beta chain amino acid sequence having at least 80% sequence identity to SEQ ID NO: 3; and/or
(c) the modified T cell further comprises a heterologous CD8 co-receptor, optionally wherein the heterologous CD8 co-receptor is CD8α.
14 . The method of claim 1 , wherein the modified T cells are autologous with respect to the individual; optionally wherein the method comprises producing the population by:
(a) obtaining peripheral blood mononuclear cells (PBMCs) from the individual;
(b) selecting T cells from the PBMCs; and
(c) modifying the selected T cells to express the heterologous TCR and optionally a heterologous CD8 co-receptor;
and further optionally wherein the bladder cancer is relapsed bladder cancer and wherein one or more of steps (a) to (c) are performed prior to relapse.
15 . A population of modified T cells comprising a heterologous T-cell receptor capable of binding to a peptide antigen of MAGE-A4, for use in the method of claim 1 .