Neural Stem Cell Based Virotherapy for Malignant Glioma

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PROJECT 1: PROJECT SUMMARY Glioblastoma remains resilient to therapy and recurrence is almost universal. In particular, targeted therapies fail given the heterogeneity in the expression or presence of molecular targets for these therapies across tumors. Oncolytic virotherapy (OV) is an anti-tumoral strategy where viruses selectively replicate and kill tumor cells in the brain and potentially, activate anti-tumoral immune response. Initial studies showed that a bottleneck for the efficacy of OV was poor distribution of virus in the human brain. To overcome this challenge, over the last SPORE funding period, we investigated the feasibility and safety of delivering oncolytic adenovirus to the peri-tumoral brain of malignant glioma patients using neural stem cells (NSC) which can carry OV, and migrate to distant tumor pockets infiltrating the brain. We conducted a Phase 1 trial in which we showed the feasibility, safety and established a maximally-tolerated dose for this therapy (NCT03072134) and published the results in Lancet Oncology. The next step in this program is to perform a phase II trial to investigate the efficacy of OV using overall survival as an endpoint for efficacy. However, a phase II trial needs to be optimized via additional studies proposed in this continuation of funding by 1) enabling multiple injections over time, to be accomplished through a novel brain parenchymal catheter-based delivery system (Renishaw ®). 2) maximizing NSC viability and OV production using N-acetylcystein Amide (NACA), which we showed to enhance delivery and efficacy of this therapy, and 3) a priori-identification of patients with tumors that are susceptible to OV. We hypothesize that only a subset of patients might have tumors that are susceptible to OV, and that identification of susceptible tumors will allow elucidation of an efficacy signal. In this continued renewal of Project 1, we now propose the following specific aims: Specific Aim 1: Conduct a phase 1B expansion trial utilizing a novel catheter method to deliver multiple injections of product in newly diagnosed malignant gliomas Specific Aim 2: Examine the pre-existing tumor microenvironment, the effect of NACA on viral replication, and the immune response during NSC-OV therapy in malignant glioma patients. Specific Aim 3: Validate genes that are implicated in glioma susceptibility to oncolytic virus using paired analysis of pre-treatment and during-treatment human glioma specimens