Potent therapeutic activity of a novel Salmonella-based cancer vaccine (P4314)

Abstract

Abstract Inadequate antigen delivery and insufficient activation of innate immunity are among major factors responsible for the failure of cancer vaccines. We recently reported a new type of an attenuated Salmonella-based oral vaccine that uses the evolutionary conserved SPI2 locus-encoded molecular machinery of Salmonella to express and translocate survivin into the cytosol of antigen-presenting cells. In order to maximize the vaccine therapeutic potential, we tested a series of SPI2 promoter/effector combinations, performed codon optimization of survivin cDNA, and used a synthetic NKT-cell ligand, 7WD8-5 as an adjuvant. We found the combination of sifB promoter with sseJ effector could enhance vaccine immunogenicity 5 fold that resulted in a much stronger antitumor activity in A20 murine lymphoma model compared with the original vaccine. The vaccine therapeutic efficacy was further enhanced by combination with 7WD8-5, resulting in complete tumor regression. The improved vaccine was also effective against established CT26 colon carcinoma tumors. Antibody depletion experiments demonstrated that the anti-tumor activity depends on both CD8 and CD4 T cells, but not NK cells. Importantly, we were able to visualize tumor infiltration with CD8 T cells that accompanied tumor regression. Therefore, antigen delivery via SPI2-regulated secretion system of Salmonella may serve as a foundation for effective cancer vaccines.