Abstract 850: Development of a systemic enveloped immunovirotherapy for targeting metastatic sites

Abstract Background: Systemic virotherapies targeting directly all tumors are a promising form of cancer immunotherapy not only due to their tumor lytic characteristics but also because of their potential to transform tumor immune microenvironment, and targeted delivery of virus-encoded therapeutic payloads into tumors. Developing a platform for systemic delivery would provide a significant advantage in treating both primary tumors and any metastatic lesions. However, systemic administration of virotherapies may pose challenges of increased toxicity and reduced efficacy due to rapid virus clearance. In order to overcome these limitations, we have selected and developed a novel enveloped vaccinia virus platform by isolating a complement-resistant strain called Redtail vaccinia virus (RT). We have further engineered the backbone of the isolated strain to achieve tumor specific targeting and high therapeutic efficacy. Methods: The RT backbone was genetically engineered by deleting multiple metabolic and immuno-modulatory genes. The replications of lead RT candidates were compared in vitro by xCELLigence real time cell analysis. In addition, therapeutic efficacy and toxicity profile of the candidate RT were monitored through in vivo imaging and clinical observation in both immunocompromised and immunocompetent mouse models. Results: The newly developed and engineered RT demonstrated significant production of enveloped viruses with improved safety profile and enhanced therapeutic efficacy in metastatic lung cancer mouse models. In the immunodeficient nude mouse model, selected RT modification showed tumor specific targeting and preferential amplification in the tumors. In immunocompetent mouse model, RT lead candidate exhibited significant survival in circulations, tumor targeting, regression of primary and metastatic tumors with acceptable safety profile. In addition, drastic changes in tumor microenvironment were observed. Enveloped RT oncolytic immunotherapy increased cytotoxic T cell infiltration and decreased Tregs at the tumor sites, along with the release of proinflammatory cytokine, ultimately leading to tumor regression. Conclusions: In summary, we have successfully developed a novel enveloped antitumor virotherepy that could be systemically delivered as a form of cancer immunotherapy in a safe manner. Citation Format: Yunyi Kang, Duong Nguyen, Trevor Smith, Stephanie Songco, Forrest Neuharth, Ivelina Minev, Karolin Streule, Selamawit Alemu, Lina Schulte, Thomas Herrmann, Boris Minev, Antonio Santidrian. Development of a systemic enveloped immunovirotherapy for targeting metastatic sites [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 850.