Ctim-38. Pioneering Quad-Targeting Car T Cell Therapy in Pediatric CNS Tumors – Analysis From the First-in-Human Phase 1 Trial Brainchild-04

BACKGROUND BrainChild-04 is a first-in-human clinical trial of quad-chimeric antigen receptor (CAR) T cell therapy for children and young adults with central nervous system (CNS) tumors. This trial administers repeated locoregional CAR T cells targeting B7-H3, EGFR, HER2, and IL-13Ralpha2 (“quad-CAR T cells”), leveraging multi-antigen targeting to address the tumor heterogeneity of high-grade CNS tumors. METHODS The primary endpoints are feasibility and safety, and secondary endpoints are disease response and correlative studies of CAR T cell activity. The trial utilized a Bayesian Optimal Interval (BOIN) statistical design with three planned dose regimens(DR). There are 2 arms with weekly delivery for 3 weeks of a 4-week cycle:(A) –diffuse intrinsic pontine glioma (DIPG), (B) –non-pontine diffuse midline glioma (DMG) or other relapsed CNS tumors. RESULTS Enrolled patients include pontine DMG or DIPG N=21, non-pontine DMG N=11 other CNS tumors N=10. Of the 42 enrolled patients, 30 have been infused with 4 awaiting infusions. A total of 164 intracranial CAR T doses have been delivered, including Arm A DR 1 (N=6), Arm B DR 1 (N=6), DR2 (N=18). The most common adverse events have been grade 1-2 fever (30/30 patients), grade 1-3 headache (29/30), and grade 1-2 nausea/vomiting (29/30). There has been 1 DLT (grade 3 acoustic nerve disorder). There has been no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity (ICANS). CTCAE and tumor inflammation-associated neurotoxicity are both being captured. Median follow up time post infusion, CAR T cell detection in CSF, radiographic response, CSF circulating tumor DNA and cytokine analysis will be presented. CONCLUSIONS Our experience suggests tolerability of locoregional delivery of quad-CAR T cells at doses currently evaluated. These data support continued evaluation of this product to better assess anti-tumor activity in patients with CNS tumors, including DIPG/DMG.