Abstract
We report preliminary data for the first subject with diffuse intrinsic pontine glioma (DIPG) treated with intracranial CAR T cells. BrainChild-03 (NCT04185038) is a phase 1 trial of repetitively-dosed locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or DIPG. DIPG patients enroll on Arm C, on which B7H3CARs are delivered into the ventricular system via a CNS reservoir catheter. This study does not use lymphodepletion. Primary endpoints are feasibility and safety, with second endpoints of disease response. This 18-year-old female (BrainChild-03 S005) with radiographically-classic DIPG and biopsy-confirmed H3 K27M mutation enrolled on Arm C after progression 552 days from diagnosis following focal radiation and temozolomide, irinotecan, and bevacizumab. Apheresis and manufacturing produced 4.2x10(9) second-generation B7H3CARs with a methotrexate-resistant human DHFR mutein (huDHFR(FS); L22F,F31S) in a single transcript in combination with the B7-H3-specific CAR and EGFRt, each separated by a T2A linker, allowing methotrexate selection and enrichment. At time of submission, she has received 10 every-other-week outpatient infusions of 1x10(7) B7H3CARs (first dose on October 2, 2020). She has had no DLTs, but has experienced grade 2 fever and grade 2–3 headache peaking ~12–48 hours after each infusion. Following the 8(th) CAR T cell infusion, she experienced increased focal weakness and dysarthria at ~72 hours with resolution after 48 hours. She has not experienced cytokine release syndrome (CRS). She has stable disease 138 days post-initial CAR T cell infusion. Frequently collected correlative studies have detected viable B7H3CARs in the CSF post-infusion via flow cytometry. CSF cytokine analysis has revealed elevations of CXCL10, GM-CSF, and G-CSF following B7H3CAR infusions, without correlation in the serum. A second evaluable subject with DIPG has also received 4 locoregional doses of 1x10(7) B7H3CARs without a DLT. She also has stable disease and detectable viable B7H3CARs in the CSF.