Advancing Extracellular Vesicle Therapy for Brain Cancer

PROJECT SUMMARY Engineered tumoricidal extracellular vehicles (EVs) are a promising therapy for the highly aggressive brain cancer Glioblastoma (GBM). Round Table Research Inc. (RTR), in collaboration with Drs. Shawn Hingtgen and Juliane Nguyen at UNC-Chapel Hill, has successfully developed the first EV drug carriers derived from induced neural stem cells (iNSCs), a unique cell type created using novel Transdifferentiation (TD) cellular reprogramming strategies, for GBM treatment. Building on the long-standing interest and deep expertise of our RTR and UNC team across EV carriers, iNSC technology, and GBM therapy, we demonstrated that 1) iNSCs produced EVs at twice the rate of parent fibroblasts; 2) iNSCs naturally loaded the pro-apoptotic agent TRAIL throughout the lumen and outer membrane of EVs (EVTRAIL) that selectively co-localized with tumor foci and killed a panel of co-cultured brain cancer cells; 3) the intracranial infusion of EVTRAIL therapy reduced metastatic brain cancer 500-fold greater than free drug; 4) Mimicking key aspects of clinical EV therapy for GBM, EVTRAIL therapy reduced tumor volumes 50-fold while extending median survival from 39 to 60 days with 30% long-term survivors in mice bearing diffuse patient-derived GBMs. These results demonstrated that iNSC-derived EVs are a platform for creating tumor-homing cytotoxic therapies for cancer, where the scalable, efficient, and efficacious production could maximize treatment durability in human trials. Thus, the proposed studies in this Phase I STTR will advance EV therapy towards the pre-IND stage. To this end, our Specific Aims are: 1) Using a scalable manufacturing process, conduct pre-IND-enabling toxicity, biodistribution and safety studies in human GBM xenograft models of resection/recurrent in mice; 2) Determine the efficacy of intracerebroventricular re-dosing of multi-agent EV therapy in post-surgical models of human GBM xenografts. The metric of success of this Phase I is to 1) confirm the efficacy of multi-drug EV therapy in a more clinically relevant setting; 2) develop an infusion, efficacy, and safety package that will guide definitive safety/toxicity that RTR will submit to the FDA as part of an IND filing. The Phase I mechanism is appropriate for this project, based on: 1) pre-clinical testing in multiple in vitro and in vivo studies have shown the safety and efficacy of iNSC-derived EV therapy for GBM, 2) the proposed studies seek to advance our approach and establish key parameters for dosing and drug composition as we work towards definitive IND-enabling studies; and 3) the dire need for an FDA-approved product to improve the extremely poor survival outcomes of GBM. Success of the proposed studies will further support pre-clinical development of this innovative approach to EV therapy for GBM and ready RTR to perform IND-enabling studies in testing in a Phase II proposal.