Abstract BACKGROUND BrainChild-03 is a first-in-human clinical trial that completed the phase 1 component of repeatedly dosed intraventricular B7-H3 CAR T cells to children with diffuse intrinsic pontine glioma (DIPG) without lymphodepleting chemotherapy. METHODS We report on BrainChild-03 Arm C, patients with DIPG receiving up to 10x10^7 B7-H3CAR T cells/dose. Primary endpoints were feasibility and safety. Secondary endpoints were disease response and correlatives of CAR T activity. RESULTS 23 patients enrolled. All had successful CAR T manufacturing. 21 patients were treated; 17 received sufficient doses for safety evaluation (4 doses/8 weeks) without a dose limiting toxicity (DLT). 4 other treated patients include: 1 patient DLT (pontine hemorrhage 8 days post-initial dose) and 3 unevaluable patients (2 discontinued protocol therapy for rapid progression; 1 did not meet eligibility to begin treatment). Overall, patients received 224 doses (median: 7, range: 1-60). Common adverse events included headache, nausea/vomiting, and fever. Of 21 treated patients, 11 enrolled after progression and survived 9.7 months (range: 6-16.9) after initial CAR T cell infusion. Of the 10 patients enrolled prior to progression, the overall survival is 16.9 months (range: 7.6-40.5) with 5/10 patients still alive. Three patients are alive 3 years from diagnosis, including 2 patients still on protocol therapy. Patients were not allowed to receive other anti-tumor agents, radiation, or surgical debulking while on protocol therapy. Circulating CSF CAR T cells were identified in 18/21 (85.7%) of patients and elevations in chemokine/cytokines associated with T cell activation and migration, including CXCL10 and IFNy. CONCLUSIONS Repeated intraventricular B7-H3 CAR T cell dosing is feasible and tolerable for children with DIPG, even after progression, with evidence of local immune activation. Early signals of survival extension underscore the potential for clinical benefit and the consideration to advance to phase 2 multi-site clinical trials.
