1374 Virus-like DNA, a single-agent poly-functional therapeutic platform that potently activates anti-cancer protective immunity

BackgroundCombination immune therapy has demonstrated curative potential in multi-agent pre-clinical studies and early clinical studies. We have created a single-agent combination immune therapy platform, dubbed virus-like DNA (VLD), to activate multiple anti-cancer immune signals leveraging the robust T cell responses elicited by viral infection. VLD was designed to avoid neutralizing antibody responses, immunotherapy-mediated toxicities, and extensive manufacturing cost and time. VLD comprises of a) antigen, composed of a polytope selected based on genomic variants to activate CD4+ and CD8+ T cells, b) a proprietary protein that activates three independent T helper 1 and cytotoxic T cell signaling pathways, and c) a proprietary dual CTLA-4/PD-1 engaging agent. We hypothesized that a rationally-designed combination of different classes of immune modulating factors will elicit tumor antigen-specific effector T cell responses and eradicate established tumors.MethodsMice were implanted with tumor cells prior to treatment with VLD. VLD expressing immunomodulators and predicted T cell epitopes was administered intravenously to tumor-bearing mice. Tumor measurements and animal health were monitored for the ensuing 2 months, upon which, surviving animals were rechallenged with tumor cells.ResultsIntravenous administration of VLD to animals with established tumors completely eradicated or significantly delayed tumors in recipient animals. Combining VLD with anti-PD-L1 far outperformed anti-PD-L1 alone which was not significantly better than untreated controls. Furthermore, rechallenge of tumor-free animals with tumor cells demonstrated complete protection 60 days after initial challenge, suggesting VLD-mediated formation of immunological memory. VLD’s combination of immunomodulators uniquely activated splenic effector memory and antigen-reactive CD8+ T cells.ConclusionsThese data suggest that VLD provides a scalable, modular, rapid, robust, and cost-effective means of inducing a durable anti-tumor host response by harnessing critical components of vaccines and gene therapies into one immunogene product to eradicate cancer by activating antigen-reactive T cells.