Leveraging Zika virus and the immune system to treat glioblastoma.

Glioblastoma (GBM) kills most adults within 2 years. One reason for inevitable recurrence is that GBM stem cells (GSCs) are resistant to existing therapies. Additionally, GBM is the hallmark example of an immunotherapy-resistant tumor. Since GSCs share properties with neural stem cells, we investigated whether the natural honing and lytic activity of Zika virus (ZIKV) could be harnessed to target and kill GSCs. We published the first use of ZIKV to kill GSCs: ZIKV kills GSCs in tumors removed from patients, with minimal impact on non-GSC tumor cells and importantly, normal human brain cells were not affected by ZIKV. In vivo, ZIKV more than doubled median survival in immunocompetent mice bearing orthotopic gliomas, and in 40-50% of cases, mice were cured. In new unpublished work, we assessed brains of mice treated with ZIKV and found that treatment induces a robust inflammatory response. Using MHC-I tetramers presenting ZIKV envelope (E) protein or luciferase peptides (expressed in the tumor cells), we found that CD8+ T cells in the region of the tumor respond to both ZIKV and tumor, and anti-tumor CD8+ T cells are increased after ZIKV infection compared to vehicle. Additionally, cured mice were protected against tumor rechallenge, suggesting ZIKV induces immunologic memory that can surveil against recurrence. Using blocking antibodies, we discovered that CD8+ T cells are required for the efficacy of ZIKV, and CD8+ T cells are required for long-term protection. Our findings suggest that ZIKV may be an effective therapy for GBM for two reasons: its direct targeting of treatment-resistant tumor cells in turn produces an antitumor inflammatory response. Such a response may now be further leveraged by immunotherapies. Citation Format: Arijita Jash, Jennifer Govero, Sharmila Nair, Michael S. Diamond, Milan G. Chheda. Leveraging Zika virus and the immune system to treat glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A13.