Phase 1 trial of intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline glioma

H3K27 M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2. CAR T cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. A phase 1 trial at Stanford University School of Medicine evaluated sequential intravenous (IV) infusion of GD2-CART in H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) patients, followed by intracerebrovascular (ICV) intracranial infusion of GD2-CART in patients with clinical or imaging benefit. Among 13 included patients, 11 received IV infusion, and 9 received ICV infusion, with no dose-limiting toxicities. All patients experienced tumor inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major tumor volume reductions (52, 54, 91, and 100%) with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months. Nine patiënten demonstrated neurological benefit. The authors conclude that sequential IV, followed by ICV GD2-CART, induced tumor regressions and neurological improvements in patients with DIPG and those with sDMG.