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

Abstract

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