Repetitive ICV administration of B7-H3 CAR T cells was conducted in a first-in-human trial in children and adolescents with DIPG (n=21). Most AEs were of grade 1 or 2, while one grade 4 event (intracranial hemorrhage) occurred at dose level 2 of 4. Median survival following infusion was greater in patients treated before progression vs. after (13.6 vs. 9.4 months, median 10.3), and 3 patients were still alive >40 months from diagnosis. MRI imaging confirmed 1 PR (6%), 15 SD (83%), and 2 PD (11%). In the CSF, CAR T cells were detectable in 72% of patients, while CXCL10, IFNγ, GM-CSF, and TARC were consistently upregulated post-infusion.
Contributed by Morgan Janes
ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG. The primary objectives were to assess feasibility and tolerability, which were both met. Secondary objectives included assessments of CAR T cell distribution and survival. A total of 23 patients with DIPG enrolled, and 21 were treated with repeated doses of ICV B7-H3 CAR T cells using intra-patient dose-escalation regimens without previous lymphodepletion. Concurrent tumor-directed therapy, including re-irradiation, was not allowed while on protocol therapy. We delivered a total of 253 ICV doses and established the highest planned dose regimen, DR4, which escalated up to 10 × 107 cells per dose, as the maximally tolerated dose regimen. Common adverse events included headache, fatigue and fever. There was one dose-limiting toxicity (intratumoral hemorrhage) during DR2. For all treated patients (n = 21), the median survival from their initial CAR T cell infusion was 10.7 months and the median survival from diagnosis was 19.8 months with 3 patients still alive at 44, 45 and 52 months from diagnosis. Ultimately, this completed first-in-human trial shows that repetitive ICV dosing of B7-H3 CAR T cells in pediatric and young adult patients with DIPG is tolerable, including multiyear repeated dosing, and may have clinical efficacy that warrants further investigation on a multisite phase 2 trial. ClinicalTrials.gov registration: NCT04185038 .
Author Info: (1) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. nicholas.vitanza@seattlechildrens.org. Department o
Author Info: (1) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. nicholas.vitanza@seattlechildrens.org. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. nicholas.vitanza@seattlechildrens.org. Seattle Children's Therapeutics, Seattle, WA, USA. nicholas.vitanza@seattlechildrens.org. (2) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. Seattle Children's Therapeutics, Seattle, WA, USA. (3) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (4) Seattle Children's Therapeutics, Seattle, WA, USA. (5) Seattle Children's Therapeutics, Seattle, WA, USA. (6) Seattle Children's Therapeutics, Seattle, WA, USA. (7) Seattle Children's Therapeutics, Seattle, WA, USA. (8) Seattle Children's Therapeutics, Seattle, WA, USA. (9) Seattle Children's Therapeutics, Seattle, WA, USA. (10) Seattle Children's Therapeutics, Seattle, WA, USA. (11) Seattle Children's Therapeutics, Seattle, WA, USA. (12) Seattle Children's Therapeutics, Seattle, WA, USA. (13) Seattle Children's Therapeutics, Seattle, WA, USA. (14) Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (15) Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (16) Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (17) Division of Neurosurgery, Seattle Children's Hospital and Department of Neurological Surgery, University of Washington, Seattle, WA, USA. (18) Division of Neurosurgery, Seattle Children's Hospital and Department of Neurological Surgery, University of Washington, Seattle, WA, USA. (19) Division of Neurosurgery, Seattle Children's Hospital and Department of Neurological Surgery, University of Washington, Seattle, WA, USA. (20) Division of Neurosurgery, Seattle Children's Hospital and Department of Neurological Surgery, University of Washington, Seattle, WA, USA. (21) Division of Neurosurgery, Seattle Children's Hospital and Department of Neurological Surgery, University of Washington, Seattle, WA, USA. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. (22) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (23) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (24) Department of Radiology, Seattle Children's Hospital, Seattle, WA, USA. (25) Department of Radiology, Seattle Children's Hospital, Seattle, WA, USA. (26) Department of Pediatrics, Program of Solid Tumors, University Clinic of Navarra, CIMA-Universidad de Navarra, Pamplona, Spain. (27) Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, New South Wales, Australia. Precision Medicine Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia. Paediatric Stream, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine and Wellbeing, Newcastle, New South Wales, Australia. (28) Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. (29) Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (30) Department of Pharmacy, Seattle Children's Hospital, Seattle, WA, USA. (31) Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (32) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (33) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (34) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. (35) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. Seattle Children's Therapeutics, Seattle, WA, USA. (36) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. Seattle Children's Therapeutics, Seattle, WA, USA. (37) Seattle Children's Therapeutics, Seattle, WA, USA. (38) Seattle Children's Therapeutics, Seattle, WA, USA. (39) Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA, USA. (40) Seattle Children's Therapeutics, Seattle, WA, USA. (41) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. Seattle Children's Therapeutics, Seattle, WA, USA. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. (42) Seattle Children's Therapeutics, Seattle, WA, USA.
