A first-in-human phase I trial, BrainChild-03 (NCT04185038), has shown promising early results for intraventricular B7-H3 CAR T-cell therapy in children with diffuse intrinsic pontine glioma (DIPG) and other recurrent/refractory central nervous system (CNS) tumors. The study, which administered repeated locoregional B7-H3 CAR T cells, reported no dose-limiting toxicities and observed sustained clinical and radiographic improvement in one patient with DIPG.
DIPG remains a highly aggressive and uniformly fatal pediatric brainstem tumor, creating an urgent need for innovative therapeutic strategies. B7-H3 (CD276) is a protein expressed on many CNS tumors, making it a potential target for CAR T-cell therapy.
The BrainChild-03 trial enrolled three evaluable patients with DIPG, including two who had progressed after initial treatment. These patients received a total of 40 infusions of B7-H3 CAR T cells. The study found the treatment to be well-tolerated, with no dose-limiting toxicities observed. Notably, one patient experienced sustained clinical and radiographic improvement, which lasted for 12 months.
Immune Activation and CAR T-Cell Persistence
Further analysis revealed correlative evidence of local immune activation in the patients, as well as the persistence of B7-H3 CAR T cells in the cerebrospinal fluid (CSF). Targeted mass spectrometry of CSF biospecimens showed modulation of B7-H3 and critical immune analytes, including CD14, CD163, CSF-1, CXCL13, and VCAM-1. These findings suggest that intracranial delivery of B7-H3 CAR T cells can induce local immune activation within the CNS microenvironment.
Implications for DIPG Treatment
These preliminary results indicate the feasibility and potential of repeated intracranial B7-H3 CAR T-cell dosing for DIPG. The observed clinical response and immunological changes warrant further investigation in larger clinical trials. The study also demonstrates the utility of serial mass spectrometry for monitoring treatment response and understanding the complex interplay between CAR T cells and the tumor microenvironment within the CSF.
The research team emphasizes that these are early findings and further studies are needed to fully evaluate the safety and efficacy of this approach. However, the initial results offer a glimmer of hope for children with this devastating disease.
