Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer

• Published in: Cancer immunology research Vol. 1; no. 2; p. 123
• Main Authors: Binder, David C, Engels, Boris, Arina, Ainhoa, Yu, Ping, Slauch, James M, Fu, Yang-Xin, Karrison, Theodore, Burnette, Byron, Idel, Christian, Zhao, Ming, Hoffman, Robert M, Munn, David H, Rowley, Donald A, Schreiber, Hans
• Format: Journal Article
• Language: English
• Published: United States 01.08.2013
• Subjects: Animals; Antigen Presentation; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Bacterial Vaccines - genetics; Bacterial Vaccines - immunology; Bacterial Vaccines - pharmacology; Cancer Vaccines - genetics; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CD8-Positive T-Lymphocytes - immunology; Epitopes; Female; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating - immunology; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Ovalbumin - immunology; Ovalbumin - pharmacology; Peptide Fragments - immunology; Peptide Fragments - pharmacology; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; CD8+ T cell rescue; PD-L1; Tumor rejection; vaccine; S. Typhimurium
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-13-0058

Immunogenic tumors grow progressively even when heavily infiltrated by CD8(+) T cells. We investigated how to rescue CD8(+) T cell function in long-established immunogenic melanomas that contained a high percentage of endogenous PD-1(+) tumor-specific CD8(+) T cells that were dysfunctional. Treatment with αPD-L1 and αCTLA-4 blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8(+) T cell response: proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8(+) T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1 blocking antibody enhanced the expansion of tumor-specific CD8(+) T cells and resulted in 80% tumor rejection. Collectively, these data demonstrate a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8(+) T cells and eradicate advanced immunogenic tumors.