MODL-14. MODELING THE INTRATUMORAL HETEROGENEITY OF AGGRESSIVE GLIOBLASTOMA ON ORGANOTYPIC BRAIN SLICES TO OPTIMIZE TUMOR-HOMING TUMORICIDAL INSC TREATMENT

Abstract BACKGROUND Tumor-homing tumoricidal neural stem cell (tNSC) therapy is a promising new strategy that recently entered human patient testing for glioblastoma (GBM). Developing strategies tNSC to overcome intratumoral heterogeneity, variable cancer invasiveness, and differential drug response of GBM will be essential efficacious treatment in the clinical setting. We sought create novel hybrid tumor models investigate impact heterogeneity on durability. METHODS utilized organotypic brain slice explants cells with varied properties generate heterogeneous ex vivo vivo. first investigated durability mono- combination primary NSCs fibroblast-derived induced (iNSCs) engineered necrosis factor-related apoptosis-inducing ligand (TRAIL) or enzyme-prodrug therapy. Next, we molecular assays explore mechanisms driving adaption escape. RESULTS Non-invasive imaging, assays, immunohistochemistry showed recapitulated key aspects disease. Testing multiple tNSC-TRAIL robust initial inhibitions growth significantly increased survival. However, tumors rebounded patterns regrowth therapeutic, dose, route administration. found adjusting iNSC delivery spatiotemporal TRAIL coverage decreased volume throughout brain, reducing burden 100-fold as quantified live slices resulting median survival across both solid invasive tumors. CONCLUSIONS These studies report accurately capture which markedly while demonstrating ability certain kill.