210. Complete Control of Tumor Growth In Vivo By a Synthetic Consensus Multi-Antigen DNA Immune Therapy for Prostate Cancer

Abstract

Prostate cancer (PCa) is one of the leading causes of cancer deaths among men with limited treatment options. Accordingly, new approaches, such as immunotherapy, may represent important approaches for PCa treatment. Electroporation (EP) delivered DNA vaccines has recently shown promising results for therapeutic treatment of HPV early disease in humans. Application of this technology for PCa immunotherapy strategies has been limited to single antigen and epitope targets with limited success. We hypothesized that a broader collection of antigens adjuvanted by plasmid encoded IL-12 would bypass immune tolerance and improve the breadth and effectiveness of a PCa immunotherapy approach. We tested this hypothesis in NHP for immune tolerance effects as well as in the highly relevant TRAMP-C2 challenge model. We developed highly optimized DNA vectors encoding consensus antigens for important PCa targets prostate-specific antigen (SynCon PSA), prostate-specific membrane antigen (SynCon PSMA), and human six-transmembrane epithelial antigen of the prostate (STEAP). In mice the vaccines demonstrated potent IFNγ production by ELISpot (2740 SFU) and robust immune responses in the CD4+ (0.53%) and CD8+ (3.0%) T cell compartments. Further, sera from immunized mice reacted in ELISA with relevant targets and specifically stained LNCaP cells, a human PCa cell line, as well as human PCa tumor sections, supporting that the vaccine antigens induced relevant antibody responses. Vaccination of Rhesus Macaques, which share greater than 98% identity with humans, showed robust anti-PSA, PSMA and STEAP IFNγ production (612 SFU), potential for cytotoxic T cell function, and antigen specific seroconversion supporting the ability of these constructs to break tolerance. The therapeutic potential of PSMA, STEAP, and the combination of PSMA and STEAP, alone or with the molecular adjuvant IL-12, was evaluated in mice in the TRAMP-C2 tumor model. Alone, PSMA, STEAP or PSMA+STEAP demonstrated prolonged survival and a modest impact on tumor growth. However, the combination of synthetic vaccine antigens with IL-12 resulted in 100% efficacy in treatment and clearance of tumors resulting in 100% survival. These data support further study of this novel immune therapy of PCa.