ID #510 Intraventricular delivery of IL13Rα2-targeting CAR T cells in pediatric and young adult patients with recurrent or refractory central nervous system tumors: results of a Phase 1 trial

Abstract Outcomes for high-grade pediatric brain tumors are poor,butthere is optimism that chimeric antigen receptor (CAR) T cell therapycan improve prognosis. We present results from the firsttwo cohorts of a phase I clinical trial of IL13BBζ-CAR T cellsinfused weekly into the cerebral ventricles for children and young adults with recurrent or refractory high-grade neuromalignancies. Results Among the 18 patients (ependymoma =5, DIPG/DMG =9, pHGG=4) treated on trial, patients in cohort 2 (n = 15) received systemic lymphodepletion prior to first infusion; cohort 1 (n = 3) patients did not. The trial met its primary objectives of establishing feasibility, safety, and tolerability. There was one dose-limiting toxicity (Gr3 hypoxia, cohort 2). Secondary objectives included CAR T cell distribution and persistence in CSF and peripheral blood, response rates by RAPNO criteria, and overall survival. Patients received a median of 8 (range: 2-19) infusions. Common adverse events included headache, fever, and fatigue. Patients receiving lymphodepletion also experienced cytopenias. Two patients met protocol criteria for radiographic response, and half experienced radiographic decreases consistent with an anti-tumor response. Median overall survival from diagnosis for patients receiving lymphodepletion was 187m for patients with ependymoma, 20.5m for patients with midline glioma, and 30m for other patients. Median overall survival was 36m from diagnosis for patients not receiving lymphodepletion. Importantly, patients who did not receive lymphodepletion developed anti-CAR humoral and cellular immune responses detectable in the CSF and peripheral blood, and patients receiving lymphodepletion had higher numbers of CAR+T cells detected in CSF over the course of therapy. Conclusions This study demonstrates the safety, tolerability, and biological activity of locoregionally-delivered IL13BBζ-CAR T cells for children and young adults with neuromalignancies. Moreover, we show anti-CAR immune responses in patients not receiving lymphodepletion, but not in patients receiving systemic lymphodepletion. ClinicalTrials.gov:NCT04510051.