First-in-human quad-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial.
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Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are lethal pediatric central nervous system (CNS) tumors with a median survival of 11 months. Despite advancements in translating chimeric antigen receptor (CAR) T cells for these patients, efficacy may be constrained by antigen heterogeneity and immune escape. We conducted a first-in-human, phase 1 trial (BrainChild-04; NCT05768880) evaluating repetitive intracerebroventricular (ICV) administration of a multi-antigen targeting CAR T cell product directed against B7-H3, EGFR806, HER2 and IL13Rα2 (quad-CAR T cells) for children and young adults with DIPG/pontine DMG (Arm A) and recurrent or refractory CNS tumors (Arm B). Here we report results from Arm A. Primary endpoints were feasibility, safety, and determination of the maximally tolerated dose regimen (MTDR). Secondary endpoints included CAR T cell distribution and preliminary clinical activity. Correlative analyses assessed CAR T cell kinetics and cytokine dynamics in cerebrospinal fluid (CSF). Twenty-six patients were enrolled with 100% manufacturing success rate. Twenty-one patients received at least one infusion (median 8/patient, range 3-56). No dose-limiting toxicities occurred in the dose-finding period, and treatment was tolerable with predominantly grade 1-2 adverse events, including fever (95%), headache (86%), and fatigue (81%). One dose-limiting toxicity (acoustic nerve disorder) occurred outside the evaluation window. Repetitive ICV dosing was feasible, and most of the infused patients (86%) initiated two or more treatment courses (median 4). CAR T cells were detected in CSF in 100% of patients, across serial courses in 76% of patients, with evidence of detection across sequential courses, particularly at higher dose levels. Cytokine profiling demonstrated dynamic immune activation within the CNS. Median survival from initial CAR T infusion was 8.6 months (95% CI: 5.2-10.3). All deaths were due to disease progression. Repetitive ICV administration of quad-CAR T cells is feasible and tolerable in children and young adults with DIPG/DMG. This study represents the first clinical application of quad-antigen targeting CAR T cells and confirmed feasibility in manufacturing and preliminary evidence of biologic activity in the CNS. These findings support further evaluation of multi-antigen CAR T strategies to address tumor heterogeneity of antigen expression as a likely barrier to CAR T cell efficacy in patients with CNS tumors.