Antigen-Specific Bacterial Vaccine Combined with Anti-PD-L1 Rescues Dysfunctional Endogenous T Cells to Reject Long-Established Cancer

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 alpha PD-L1- and alpha CTLA-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 (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 alpha PD-L1-blocking antibody enhanced the expansion of tumor-specific CD8(+) T cells and resulted in 80% tumor rejection. Collectively, these data show a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8(+) T cells and eradicate advanced immunogenic tumors. (C) 2013 AACR.