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Sharmila Nair, Milan Chheda, Michael S Diamond, Advancing Immunovirotherapy with Zika virus to treat high-grade brain tumors, The Journal of Immunology, Volume 210, Issue Supplement_1, May 2023, Page 245.10, https://doi.org/10.4049/jimmunol.210.Supp.245.10
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Abstract
High-grade brain tumors such as glioblastoma multiforme (GBM) are the most aggressive primary brain tumor and virtually all patients die within 2 years of diagnosis. Poor patient outcomes are caused by two known factors. First, presence of GBM stem cells (GSCs) which are a subpopulation of tumor cells that are resistant to radiation treatment and chemotherapy. GSCs drive tumor initiation and are the primary cause for tumor relapses. Currently, no treatment consistently kills these highly resistant cells. Second, the cold tumor microenvironment is filled with anti-inflammatory T cells and myeloid suppressor cells contributing to a weak anti-tumor immunological response. Oncolytic viral treatments are considered an attractive treatment option for high-grade solid tumors as they are engineered to replicate and destroy transformed cells as well as improve inflammatory immune responses against the tumor. However, none are specifically designed to kill GSCs. We previously tested and demonstrated that the natural tropism of Zika virus (ZIKV) can be harnessed to target and kill GSCs.
In vivo we demonstrated that intratumoral ZIKV treatment was enough to improve the survival outcomes of glioma bearing mice up to 40–60%. Importantly the oncolytic action of ZIKV extended beyond its anti-GSC effects. Reduction in tumor size and improved survival outcomes following oncolytic ZIKV treatment was caused by Perforin 1 activity in CD8+ T cells which clears tumor components not directly killed by ZIKV. In preliminary studies we observed that DC-2 and CCR2+ antigen presenting cell (APC) subsets are utilized by ZIKV to drive CD8+ T cells against GBM. This highlights the immunological barriers of GBM that can be overcome with ZIKV immunovirotherapy.
