Abstract B016: Prime-Boost: mRNA Tumor Vaccines in Combination with Oncolytic Virotherapy for Durable Anti-Tumor Immunity

Abstract Tumor vaccines have shown clinical promise in certain cancers, but their long-term efficacy is limited by two key challenges: 1) the immune-suppressive tumor microenvironment (TME), and 2) the selective targeting of antigen-positive tumor cells by the vaccine, which can lead to the overgrowth of antigen-negative tumor cells and relapse. To overcome these barriers, we investigated a combination approach using mRNA tumor vaccines alongside oncolytic virotherapy in HPV and HER2 mouse tumor models. Our results indicate that while mRNA vaccines effectively eradicate antigen-positive tumors and inhibit their growth, resistance develops rapidly, allowing tumors to escape the vaccine's effects. However, when mRNA vaccination was followed by intratumoral treatment with an oncolytic virus, with or without the expression of HPV or HER2 antigens, we observed significantly more durable anti-tumor responses in both models. The oncolytic virus induced a broad and dynamic tumor antigen presentation through its lytic infection, effectively lysing tumor cells and releasing a wide variety of tumor-associated antigens. This process not only increased the antigenic load within the tumor but also reprogrammed the TME, shifting it from an immune-suppressive environment to one more conducive to anti-tumor immune activity. The combination of mRNA vaccination and oncolytic virotherapy resulted in a strong local immune response, driven by the enhanced antigen presentation from the viral infection. In addition, the alteration of the TME allowed the systemically established anti-tumor immunity—generated by the mRNA vaccine—to penetrate and act within the tumor microenvironment, overcoming the previous immune barriers. We also observed the generation of systemic antigen-specific T-cells, and animals showed resistance to subsequent tumor challenges, indicating the development of immune memory. These findings highlight the unique role of oncolytic virotherapy as an intratumoral “boost” agent, capable of inducing a broader range of tumor antigens through the lysis of tumor cells, while simultaneously altering the TME to support and amplify the action of the systemically delivered tumor vaccine. When combined in a prime-boost regimen, these two approaches synergize to generate a robust, durable anti-tumor immune response that is both localized within the tumor and systemically protective against recurrence. In summary, our study demonstrates that the combination of mRNA tumor vaccines and oncolytic virotherapy offers a powerful strategy to enhance tumor antigen presentation, reshape the TME, and overcome immune evasion mechanisms, providing a promising approach for achieving durable anti-tumor immunity. Citation Format: WILLIAM JIA. Prime-Boost: mRNA Tumor Vaccines in Combination with Oncolytic Virotherapy for Durable Anti-Tumor Immunity [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B016.