EXTH-21. WINNING THE TUG OF WAR BETWEEN VIRUS AND TUMOR IMMUNODOMINANCE IN GLIOMAS TREATED WITH ONCOLYTIC ADENOVIRUSES USING TOLEROGENIC STRATEGIES

Abstract Phase 1 and 2 clinical trials of our oncolytic adenovirus Delta-24-RGD for patients with recurrent malignant gliomas have demonstrated its safety and efficacy, and showed that 20% of the patients experienced long-term tumor remissions often associated with inflammatory responses and tumor infiltration of lymphocytes. Based on our preliminary data, we expected that the most frequent tumor-infiltrating CD8+ T cell clones will target adenoviral hexon, with a single virus-specific clone representing up to 5% of the total population. Competition between T cells for resources may limit the expansion of subdominant clones recognizing tumor antigens. We hypothesized that mitigating virus-specific immunity allows the expansion of tumor-specific T cells and results in better therapeutic efficacy. In mice, intravenously injected nanoparticles encapsulating adenoviral antigens preferentially accumulated in the liver (P<0.0001), where self-reactive immune cells are deleted through peripheral tolerance. RNA-sequencing of antigen-specific T cells isolated after nanoparticle injection revealed enriched expression of gene sets involved in immune tolerance through clonal deletion and T cell anergy, including increased expression of immune checkpoint molecules (P<0.001). In glioma-bearing mice treated with virotherapy in combination with nanoparticle administration, tumor infiltrating lymphocytes exhibited decreased IFNγ secretion against viral antigens and increased secretion against tumor antigens, suggesting a redirection of the immunity from anti-viral to anti-tumoral (P<0.05). Importantly, virotherapy with nanoparticles increased the overall survival of tumor-bearing mice compared to virus treatment alone (P<0.001). To further characterize the roles of virus- and tumor-specific immune cells during virotherapy we are analyzing the T cell receptor repertoire of surgical specimens from nine glioma patients treated with Delta-24-RGD in a phase 1 clinical trial. In summary, our data provide the basis for a future clinical trial using tolerogenic strategies to redirect immunodominance of the viral to the glioma antigens, and represent a novel strategy to enhance anti-tumor immunity during virotherapy of brain tumors.