CAR-T cell therapy for diffuse intrinsic pontine glioma clinical trials
Recent Clinical Trials and Developments
BrainChild Bio's BCB-276: BrainChild Bio is advancing BCB-276, an autologous CAR-T cell therapy targeting B7-H3, a protein commonly expressed on CNS tumors. Following a positive meeting with the U.S. Food and Drug Administration (FDA), the company plans to initiate a multi-center Phase 2 pivotal clinical trial by the end of 2025. This decision is based on encouraging safety and efficacy data from a Phase 1 trial conducted at Seattle Children’s Hospital, involving 21 patients who received repeated doses of the therapy.
Stanford Medicine's GD2-CAR T Cell Therapy: A clinical trial at Stanford Medicine investigated GD2-targeting CAR-T cells in children with DIPG and spinal diffuse midline gliomas. Of the 11 participants treated, nine exhibited clinical benefits, including tumor reduction and improved neurological function. Notably, one patient experienced a complete response, with the tumor disappearing from brain scans and remaining healthy four years post-diagnosis.
GD2CART Phase 1 Trial: The National Cancer Institute is conducting a Phase 1 trial (NCT04196413) to assess the safety and optimal dosing of autologous GD2 CAR-T cells in patients with DIPG or spinal diffuse midline gliomas. This study aims to evaluate the therapy's side effects and therapeutic potential.
B7-H3 CAR T Cells in BrainChild-03 Trial
Seattle Children's Hospital has been conducting the BrainChild-03 trial, delivering repeated doses of intraventricular B7-H3 CAR-T cells to children with recurrent or refractory CNS tumors, including DIPG. Preliminary results indicate feasibility and tolerability, with evidence of local immune activation.
Vitanza et al. conducted 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.
They 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 1).
The BrainChild-03 trial represents a significant milestone in the treatment of DIPG, demonstrating that repetitive ICV administration of B7-H3 CAR T cells is feasible and tolerable. The survival outcomes and long-term survivors provide hope for a condition historically considered untreatable. However, the study's limitations, including its single-center design, small sample size, and lack of a control group, underscore the need for further investigation. The promising results justify advancing to a multisite phase 2 trial to explore the full potential of B7-H3 CAR T cell therapy for DIPG.