Validation of a novel treatment for glioblastoma using oncolytic Zika virus

Project Summary / Abstract Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor with no known cure. GBM is projected to account for almost 14,500 new cases and approximately 10,000 deaths in the United States (U.S.) in 2023. The prognosis for patients afflicted with GBM is incredibly poor, with a median survival of approximately 8 months and less than 5% of patients surviving 5 years. Although therapies for GBM exist, these poor outcomes are a direct testament to the treatment challenges. The difficulty in treating GBM is due to several factors. 1) Treatments must cross the blood brain barrier (BBB) - this constrains the molecular properties of prospective drug candidates. 2) Treatments must be agnostic to cell type so GBM cells are preferentially targeted over healthy cells. 3) GBM tumors often contain a population of glioma stem cells which are highly resistant to radiation and chemotherapy. 4) The immunoinhibitory tumor microenvironment of GBM renders traditional immunotherapy approaches ineffective. Due to these challenges GBM treatment has remained largely unchanged for almost 20 years; the current standard of care is surgical resection followed by radiation and temozolomide (TMZ) chemotherapy. The addition of TMZ to this therapeutic strategy only extended patient survival for a few months yet it is still in use today since further developments have yet to show more dramatic survival improvements. The most promising new treatment for GBM is a specialized form of immunotherapy that utilizes oncolytic viruses (OVs). When the correct virus is chosen it can overcome the obstacles inhibiting other treatment approaches. Neurotropic viruses are able to effectively cross the BBB, and the correct virus can specifically and preferentially target GBM cells while avoiding killing healthy cells. Additionally, 50% of tumors are resistant to TMZ treatment, but OVs remain effective in these tumors. The data suggests OVs can even overcome and reverse immunosuppressive microenvironments in the tumors. We have identified two strains of Zika virus (ZIKV) that demonstrate substantial oncolytic activity and the potential for safe administration to humans. Our testing shows that these strains preferentially infect GBM cells, and they effectively and dramatically reduce GBM tumors in a mouse model. We have data suggesting these strains have a strong safety profile as well. We are incredibly enthusiastic about the therapeutic potential these strains offer. This proposal is designed specifically to complete IND-enabling experiments in order to move this novel treatment into the clinic.