IMMU-43. ZIKA VIRUS TO TREAT GLIOMA: TURNING COLD TUMORS HOT

Abstract

Abstract GBM is a hallmark example of an immunotherapy-resistant tumor. Previously, we discovered that Zika virus (ZIKV) has a natural honing capacity to specifically kill GBM stem cells (GSCs). Using two syngeneic glioma models, GL261 and CT2A, we found that in vivo intratumoral ZIKV treatment reduces tumor size and extends median survival far beyond that expected for its anti-GSC effects; additionally, approximately 50% of mice were long-term survivors. We now report that ZIKV treatment is associated with an increase in tumor-specific CD8+ T cells and activated myeloid cells expressing MHC-II and NOS2. Treatment with CD8-depleting antibody abrogates the survival advantage conferred by ZIKV, demonstrating that CD8+ T cells are required for ZIKV efficacy. Remarkably, ZIKV treatment also confers protection against tumor re-challenge 1.5 years after the original treatment, and this too is dependent on CD8+ T cells. Lastly, in a bilateral tumor implantation model, intratumoral ZIKV treatment of one tumor increases overall survival, suggesting ZIKV is efficacious because it generates a global anti-tumor response. Building on the observation that ZIKV treatment increases CD8+ T cells in the tumor bed, we combined ZIKV with α-PD1 immunotherapy. We found survival was dramatically increased compared to either treatment alone. Finally, to improve safety of potential ZIKV treatment for patients, we generated an immune-sensitized virus. This strain remains efficacious as a single agent and in combination with immunotherapy in vivo. Overall, our results suggest ZIKV treatment addresses two key problems in our current treatment of GBM: it specifically targets highly resistant GSC and initiates a potent anti-tumor immune response against the remaining tumor. Our work reveals the mechanistic basis of ZIKV efficacy and demonstrates the potential for ZIKV as a therapy for GBM.