Abstract 2914: Modulating the tumor microenvironmentwith an engineered oncolytic herpesvirus facilitates potent antitumor response

Abstract Oncolytic viruses (OV) are a promising approach to cancer treatment, whereby attenuated viruses selectively infect and kill tumors, while sparing healthy cells. Tumor antigens and cytokines released from infected cells prime and activate the immune system to generate durable antitumor responses. This inflames the tumor microenvironment and may complement immune checkpoint inhibitor (ICI) therapy. However, this synergy is yet to be demonstrated: in a randomized, double blind, phase III trial, the HSV based talimogene laherparepvec (TVEC) in combination with anti-PD1 ICI therapy failed to improve both progression free survival and overall survival relative to anti-PD1 therapy alone. This may be attributable to viral factors that promote tumor selective replication in part by suppressing antitumor immune elements. Consequently, there is an unmet need for OVs that overcome the limitations of current therapies. We previously developed a novel oncolytic HSV, DN146, optimized for maximum immune stimulation without compromising tumor selective replication. Re-engineering of the γ1 34.5 gene in DN146 permits efficient viral replication and tumor cell killing, while robustly activating STING and RIG-I. In vivo, DN146 exhibits strong immune stimulation and dendritic cell maturation, and robust clearance of metastatic lesions as compared to clinical analogues in a mouse model of triple negative breast cancer. We armed DN146 with an engineered high affinity SIRPα to further potentiate its antitumor effects by blocking the SIRPα-CD47 immune checkpoint. Antagonists of this checkpoint improve macrophage phagocytosis and T-cell recruitment to the TME. Further, CD47 blockade can improve cross presentation of tumor antigens to CD8+ T-cells. Together, these effects should cooperate with STING activation from DN146 to broadly reprogram the tumor microenvironment. When tested in a bilateral, murine colorectal cancer model, this virus achieves clearance of both locally injected and distal un-injected tumors, indicating strong local and systemic antitumor effects. Citation Format: Joseph Najjar, Geetanjali Geetanjali, Chase Kangas, Vk Gadi, Bin He. Modulating the tumor microenvironmentwith an engineered oncolytic herpesvirus facilitates potent antitumor response abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2914.