Abstract 953: Oncolytic viruses as in situ personalized tumor vaccines for durable efficacy

Tumor vaccines have shown clinical promise in treating certain cancers. However, their long-term effectiveness is often hindered by two major challenges: 1. The immune-suppressive tumor microenvironment (TME). 2. Selective targeting of antigen-positive tumor cells, which can lead to the expansion of antigen-negative cells and eventual tumor relapse. To address these challenges, we explored a combination approach using mRNA tumor vaccines and oncolytic virotherapy in HPV and HER2 mouse tumor models. Our findings reveal that while mRNA vaccines effectively eradicate antigen-positive tumors and suppress tumor growth, resistance quickly emerges, enabling tumors to evade the vaccine's effects. When mRNA vaccination was followed by intratumoral administration of an oncolytic virus—either with or without HPV or HER2 antigen expression—a significantly more durable anti-tumor response was achieved in both models. The oncolytic virus initiated broad tumor antigen presentation by lysing tumor cells, releasing diverse tumor-associated antigens, and increasing the overall antigenic load within the tumor. Furthermore, the lytic activity of the virus reprogrammed the TME, transforming it from an immune-suppressive environment into one more favorable for anti-tumor immune responses. This combination therapy elicited a potent local immune response, leveraging enhanced antigen presentation by the virus. The modified TME allowed the systemic immune response generated by the mRNA vaccine to penetrate and act effectively within the tumor. Additionally, the treatment induced systemic antigen-specific T-cell responses, and treated animals developed resistance to subsequent tumor challenges, demonstrating the establishment of immune memory. Our study highlights the unique role of oncolytic virotherapy as an intratumoral "boost" mechanism. By lysing tumor cells, oncolytic viruses amplify the range of tumor antigens presented to the immune system and reshape the TME to support robust immune activity. This synergy between mRNA vaccination and oncolytic virotherapy—when employed in a prime-boost regimen—produces a powerful and durable anti-tumor immune response that is both localized and systemically protective against recurrence. In conclusion, this research underscores the potential of combining mRNA tumor vaccines with oncolytic virotherapy to overcome immune evasion mechanisms, enhance tumor antigen presentation, and reprogram the TME, providing a promising strategy for achieving long-lasting anti-tumor immunity. Citation Format: William WEI GUO Jia. Oncolytic viruses as in situ personalized tumor vaccines for durable efficacy [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 953.