191. Development of an Effective Cancer Vaccine Platform Using Attenuated Salmonella to Deliver Recombinant Tumor-Associated Antigens

Abstract

Inadequate antigen delivery is one of the major limitations of modern cancer vaccine vectors. To overcome this challenge, we exploited Salmonella Pathogenicity Island 2 (SPI2) and its type III secretion system (T3SS) to deliver a tumor-associated antigen (TAA) of choice into the cytosol of antigen-presenting cells (APC) in situ. The goal of this study was to explore and exploit the potential of SPI2-encoded T3SS of clinically validated S. typhi strain CVD908 for construction of an effective cancer vaccine. We engineered the clinically validated S. typhi strain CVD908 to express SPI2-regulated dominant-negative oncoproteins survivin and MYCN. To adapt CVD908 to stably express recombinant antigens without antibiotic-dependent selection, we used a recently reported plasmid stabilization system that encodes the single-stranded binding protein (SSB), an essential protein in DNA metabolism, which was deleted from the bacterial chromosome. The SPI2-regulated expression cassette was then cloned into the SSB plasmid, so that the resultant construct maintained bacterial vector stability. We found that CVD908Δssb vector could effectively infects dendritic cells and induce antigen-specific CD8 T cell responses in vitro and in vivo. Furthermore, therapeutic vaccination with CVD908Δssb vector expressing survivin or MYCN produced potent antitumor activity in murine models of neuroblastoma and lymphoma. Thus, oral antigen delivery via SPI2-encoded T3SS of Salmonella typhi may provide the foundation of an effective cancer vaccine platform.Supported by grants from CPRIT (RP121035) and The Leukemia and Lymphoma Society.