Abstract 1547: IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma

Abstract Oncolytic virotherapy represents a promising yet under-explored therapeutic avenue for precision cancer treatment, particularly when tailored to tumor-specific molecular alterations. Patients with high-grade IDH-mutant astrocytomas continue to face limited treatment options and poor outcomes, emphasizing the need for novel strategies. In this study, we evaluated the therapeutic potential of rQNestin34.5v.2, an engineered oncolytic HSV-1, in the context of IDH1-R132H-mutant high-grade diffuse gliomas. We show that the IDH1-R132H mutation increases glioma susceptibility to viral infection by upregulating Nectin-1, the main HSV-1 entry receptor in gliomas. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, an essential antiviral defense pathway, creating a permissive environment that supports enhanced viral replication and increases tumor cell sensitivity to virus-induced apoptosis. In immunocompetent IDH1-R132H murine glioma models, intratumoral delivery of rQNestin34.5v.2 induced robust immune activation, marked by increased immune-cell infiltration into the tumor and systemic release of IFN-γ. However, elevated expression of poliovirus receptor (PVR-CD155) and the inhibitory immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating lymphocytes, suggested the emergence of an adaptive resistance mechanism following virotherapy. Combining rQNestin34.5v.2 with TIGIT blockade enhanced therapeutic efficacy and improved survival outcomes compared to monotherapy. Collectively, these data demonstrate that IDH1-R132H reshapes both viral entry pathways and antiviral immune defenses, identifying it as a predictive biomarker for oncolytic virotherapy response. Citation Format: Eleni Panagioti, Hunter J. Kelley, Alexander L. Ling, William Goins, Daniel Roberts, Sotiris Sotiriou, Bryan J. Iorgulescu, Karen Dixon, Michael B. Yaffe, Maria G. Castro, Sean E. Lawler, Gordon J. Freeman, Vijay K. Kuchroo, E Antonio Chiocca, Charles H. Cook. IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma 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 1547.