H3K27M-mutated DMGs are universally lethal tumors that express high levels of GD2 disaloganglioside and regress with IV and ICV GD2-CAR T cell therapy in preclinical models. Based on these preclinical results, Dr. Monje opened a clinical trial in 2020: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CAR T cell therapy in patients with biopsy-proven pontine or spinal cord H3K27M-mutated DMGs. Guided by their clinical experience with this therapy, this clinical trial now has 3 arms. In Arm A, they delivered GD2-CAR T cell therapy to subjects with DIPG and spinal cord DMG intravenously after a 3-day regimen of lymphodepleting (LD) chemotherapy (cyclophosphamide/fludarabine), followed by optional intracerebroventricular (ICV) administration if CAR T cell therapy was beneficial but the response was incomplete. Arms B and C tested ICV administration only, without (Arm B) or with (Arm C) lymphodepleting chemotherapy and delivered regularly at 4-6 week intervals until disease progression and up to 24 doses. They have sought to test safety and efficacy of CAR T cell therapy in children, adolescents, and young adults with DIPG and spinal cord DMG. This grant was co-funded through a partnership with Trial Blazers for Kids.