Introduction.Oncolytic virotherapy is a promising cancer treatment that usesreplication-competent viruses to induce cancer cell death.While clinical trialsare underway for a variety of solid tumors;success has been hampered by rapidimmune-mediated clearance/neutralization of the viral vectors, and poor viraldistribution to tumor satellitesdispersed throughout normal tissue. Neural stem cells (NSCs) are ideal cellcarriers that could overcome viral delivery hurdles due to their intrinsictumor-tropism and penetration capabilities. Our lab has established awell-characterized, non-immunogenic human NSC line that can selectivelydistribute to many different solid tumors. Most recently, we observedimpressive selectivity and penetration of peritoneal ovarian cancer metastasesafter intraperitoneal NSC administration. We have engineered our NSCs toproduce a conditionally replication-competent adenovirus, CRAd-Survivin-pk7 (CRAd-S-pk7NSCs). This virus has two notable genetic modifications: (1) a polylysine fiberaddition that enables high affinity binding to cell-surface proteoglycans, thuspromoting viral entry into the target cell;and (2) a E1A transcriptional modification which prevents viral replication inthe absence of the survivin promoter. 80% of ovarian tumors have elevatedlevels of survivin, which then drives viral replication. Clinical gradeequivalent research banks of the CRAd-

S-pk7 NSCs cells have demonstratedefficacy in orthotopic glioma models (IND 19532), and safety in a recentfirst-in-human trial (NCT03072134) but have not yet been developed for treatingmetastatic ovarian cancer. We hypothesize that NSCs can selectively distribute thisvirus to ovarian metastases, provide protection from immunemediated clearance,and achieve significant improvements in long-term survival. Ourlong-term goal is to demonstrate efficacy and safety ofCRAd-S-pk7 NSCsfor targeted selective tumor killing in patientssuffering fromstage III ovarian cancer. Methods. Human Xenograft andimmunocompetent syngeneic models ofperitoneal ovarian cancer weretreated with escalating doses ofCRAd-S-pk7 NSCs. Treatment efficacywas determined byweek 8 tumor burden and long-term survival.Pilot toxicologystudies were conducted using the highest and lowesteffective dose.Immunophenotyping was performed on treated tumorsto assess possiblemechanism-of-action. Results. We demonstrate thatCRAd-S-pk7 NSCs can improvelong-term survival in mouse models ofovarian cancer. Weidentify the LOAEL dose, demonstrated negligibletoxicity at thisdose, and confirm CRAd-S-pk7 NSC treatment causest-cellinfiltration into the tumor micro-environment (improves CD8+/FoxP3 ratio). The LOAELdose was converted to human equivalentlevels, andPre-IND package submitted.