Enhanced Delivery of Cytotoxic Neural Stem Cells for Treatment of Glioblastoma Multiforme Using an Innovative In-situ Thermogelling Hydrogel and Focused Ultrasound

PROJECT SUMMARY Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer and ~90% of GBM patients die within 24 months after diagnosis.1 Treatment options for GBM include surgery and chemoradiation however, recurrence is common, and the disease is universally fatal.2,3 Over the past 20 years, induced neural stem cells (iNSCs) have been investigated as a novel modality for the treatment of brain cancer. The ability of iNSCs to home to tumors and kill cancer cells are makes them attractive as a new approach for the treatment of GBM. Other potential challenges include the need for repeated invasive surgery for redosing or to remove the biomaterial if it is not biodegradable in nature. To address these limitations, we propose to develop a combination therapy that harnesses long-acting delivery (>90 days) of NSCs using a novel injectable and biodegradable biomaterial and a non-invasive and efficient redosing of NSCs across the blood brain barrier (BBB) using state- of-the-art focused ultrasound (FUS) technology for enhanced treatment of GBM. The Scientific Premise of these studies is that A) an injectable biodegradable hydrogel scaffold can be developed that: 1) implements a tunable/scalable manufacturing process, 2) can accommodate high concentrations of NSCs (≥106 cells/mL) with initial targeted sustained delivery of ≥3 months, and 3) is biodegradable and does not require surgical removal post administration; B) a non-invasive systemic redosing regimen of NSCs to recurring GBM using FUS to delivery NSCs across the BBB. Our central hypothesis is that sustained local delivery of NSCs ( 3 months) alone or in combination with non-invasive redosing using FUS will improve access to residual or recurring tumor cells and survival outcomes in preclinical models. This cutting-edge combined approach will be utilized to evaluate the scientific premise of our proposal in preclinical mouse models to investigate the safety and efficacy of a unique and highly innovative combinatorial technology and treatment approach to improve treatment of GBM.