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Published on: February 24, 2023
Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial
Nicholas A Vitanza1,2,3, Rebecca Ronsley4,5,6, Michelle Choe4,5
1Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. nicholas.vitanza@seattlechildrens.org.
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 .
Insights
This phase 1 trial found repetitive intracerebroventricular B7-H3 CAR T cell therapy is feasible and tolerable for pediatric patients with diffuse intrinsic pontine glioma (DIPG). Promising survival data suggest potential clinical efficacy warranting further investigation.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Neuro-oncology
Background:
- Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric central nervous system (CNS) tumor with a median survival of approximately 11 months.
- B7-H3 is a target antigen expressed on various pediatric CNS tumors, including DIPG.
- Chimeric antigen receptor (CAR) T cell therapy offers a promising avenue for targeted cancer treatment.
Purpose of the Study:
- To assess the feasibility and tolerability of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting CAR T cells (B7-H3 CAR T cells) in pediatric patients with DIPG.
- To evaluate CAR T cell distribution and survival outcomes in patients with recurrent or refractory CNS tumors, specifically DIPG.
- To determine the maximally tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this novel therapeutic approach.
Main Methods:
- BrainChild-03, a single-center, dose-escalation phase 1 clinical trial.
- 21 pediatric patients with DIPG received repeated ICV doses of B7-H3 CAR T cells with intra-patient dose escalation, without prior lymphodepletion.
- The highest planned dose regimen, DR4 (up to 10 × 10^7 cells/dose), was established as the MTD.
Main Results:
- The trial met its primary objectives, demonstrating feasibility and tolerability of repetitive ICV B7-H3 CAR T cell dosing.
- The MTD was established at DR4, with common adverse events including headache, fatigue, and fever. One DLT (intratumoral hemorrhage) occurred at DR2.
- The median survival from CAR T cell infusion was 10.7 months, and median survival from diagnosis was 19.8 months, with 3 patients surviving beyond 44 months.
Conclusions:
- Repetitive ICV dosing of B7-H3 CAR T cells is a tolerable and feasible treatment for pediatric and young adult patients with DIPG.
- The observed survival data suggest potential clinical efficacy, supporting further investigation.
- These findings warrant a multisite phase 2 trial to further evaluate the therapeutic potential of B7-H3 CAR T cells in DIPG.
