Abstract 484: Mechanisms of synergy between TGF-beta inhibitor and IL12 expression from the systemically deliverable clinical oncolytic immunotherapy VET3-TGI

Abstract Oncolytic vaccinia virus therapies actively recruit T-cells towards the tumor microenvironment. These can be combined with IL-12 expression to help enhance the immune response by stimulating Th1 cells. However, IL-12 mediated induction of IFN-gamma was also found to increase TGF-beta signaling within the tumor microenvironment.TGF-beta mediated resistance is one of the major mechanisms of immune suppression utilized across multiple solid tumor types. Blockade of TGF-beta (TGFBi) will therefore likely improve response to immunotherapy. Combining TGF-beta inhibition with IL-12 expression can maximize therapeutic benefits through simultaneously reducing immunosuppression and enhancing anti-tumor immune response. Current studies describe a vaccinia-based immunotherapy, VET3-TGI, combining enhanced systemic virus delivery to tumors and locally expressed IL-12 and TGFBi within the tumor microenvironment, for efficient control of multiple tumor models. In vivo mouse studies demonstrated potent therapeutic activity, including many CRs, even at doses several logs below equivalent clinical doses after systemic (intravenous) delivery. In addition, toxicity studies demonstrated the safety of VET3-TGI in mouse models. This data led to the selection of VET3-TGI as a lead clinical candidate and clinical testing has begun. Citation Format: Steve Thorne. Mechanisms of synergy between TGF-beta inhibitor and IL12 expression from the systemically deliverable clinical oncolytic immunotherapy VET3-TGI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 484.