Treatment of cancers using sEphB4-HSA fusion proteins
Compositions and methods are provided for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a polypeptide agent that inhibits EphB4 or EphrinB2 mediated functions. In various embodiments the methods further provide administration of a therapeutically effective amount of an immune checkpoint inhibitor. The present inventors have demonstrated that the synergistic effect of the combination of an EphB4-EphrinB2 inhibitor and checkpoint inhibitor provides superior progression-free survival (PFS) and objective response rates (ORR) patients with various cancers by activating T cell and promoting T cell and NK cell trafficking into the tumor and via migration of immune cells (e.g., CD3 and CD8) into the tumor.
1 . A method for treating a subject diagnosed with urothelial cancer, comprising the administration of a soluble Ephrin type B receptor 4-Human Serum Albumin (sEphB4-HSA) polypeptide agent that inhibits EphB4 or EphrinB2 mediated functions, in combination with an antagonistic Programmed Cell Death Protein 1 (PD-1) antibody, as a first-line therapy according to a regimen determined to achieve improved objective response rates and progression free survival as compared to a subject administered with an antagonistic PD-1 antibody, wherein the sEphB4-HSA polypeptide agent is selected from the group consisting of a polypeptide which comprises residues 16-537 of SEQ ID NO: 1 directly fused to residues 25-609 of SEQ ID NO: 2; and a polypeptide which comprises residues 16-326 of SEQ ID NO: 1 directly fused to residues 25-609 of SEQ ID NO: 2.
2 . A method according to claim 1 , wherein the cancer is refractory to treatment with platinum-based chemotherapy.
3 . A method according to claim 1 , wherein the cancer is refractory to treatment with radiation therapy.
4 . A method according to claim 1 , wherein the cancer is refractory to treatment with an immune checkpoint inhibitor.
5 . The method according to claim 1 , wherein the cancer tumors express PD-L1.
6 . The method according to claim 1 , wherein the cancer tumors express EphrinB2.
7 . The method according to claim 1 , wherein the cancer tumors express PD-L1 and EphrinB2.
8 . The method according to claim 1 , wherein the antagonistic PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab.