Project Details

Focused ultrasound control of inducible GD2 CAR T cells for pediatric brain tumors

Ali Zamat, PhD

Summary

BACKGROUND: CAR T-cell therapy has achieved remarkable success in hematologic malignancies but remains limited in solid tumors by poor infiltration, antigen heterogeneity, and dose-limiting toxicity. Among solid tumors, brain tumors have emerged as one of the most promising targets for CAR T cell therapy due to their confinement to the central nervous system. Local intratumoral infusions have shown meaningful regression in early pediatric trials, but systemic administration remains limited. GAP: Current immunotherapeutic strategies for pediatric brain tumors lack precise intracranial and locoregional control, limiting the ability to achieve metronomic CAR T cell activation necessary to sustain efficacy while preventing exhaustion and off-tumor toxicity. HYPOTHESIS: MRI-guided focused ultrasound (MRgFUS) can safely and reversibly activate inducible GD2 CAR (iCAR) T cells in the preclinical models of pediatric brain tumors, providing remote, metronomic control to sustain efficacy while minimizing exhaustion and toxicity. METHODS: This preclinical study uses primary human GD2 iCAR T cells in orthotopic pediatric brain tumor xenograft models to evaluate MR-guided focused ultrasound as a noninvasive strategy for spatial, temporal, and metronomic control of CAR T cell activation in vivo. RESULTS: Pending. IMPACT: By integrating systemic CAR T cell delivery with noninvasive, image-guided control, this work establishes a blueprint for precision-tuned locoregional immunotherapy in children with focal neuroblastoma. Metronomic sonothermogenetic dosing could preserve T cell fitness, reduce toxicity, and expand access to safe, effective brain-directed therapies.