Researchers at Seattle Children's Research Institute have reported encouraging preliminary results from a phase I clinical trial evaluating B7-H3 CAR T-cell therapy in children with diffuse intrinsic pontine glioma (DIPG), a highly aggressive and uniformly fatal brainstem tumor. The study, published in Cancer Discovery, details the first instance of repeated intracranial infusions of B7-H3-targeted CAR T cells in DIPG patients, highlighting the therapy's tolerability and potential for inducing local immune responses.
The BrainChild-03 trial (NCT04185038) enrolled children and young adults with recurrent or refractory CNS tumors, including DIPG. The interim analysis focused on three evaluable DIPG patients who received multiple intraventricular infusions of B7-H3 CAR T cells at a fixed dose of 1 × 10^7 cells. Notably, one patient experienced sustained clinical and radiographic improvement, which lasted for 12 months.
Preclinical Development and Clinical Trial Design
The B7-H3 CAR T-cell product was developed using an scFv binder derived from the MGA271 monoclonal antibody. Preclinical studies demonstrated potent antitumor activity against B7-H3-positive CNS cancer models. The clinical trial employed a novel methotrexate (MTX) selection step during CAR T-cell manufacturing, utilizing a human dihydrofolate reductase (DHFR) mutein to purify the transduced T-cell population.
In the BrainChild-03 trial, patients with DIPG received CAR T cells via a CNS catheter directed into a lateral ventricle. Lymphodepletion was not used to facilitate repeated dosing. The primary endpoint was safety, with secondary endpoints including clinical and neuroimaging outcomes.
Tolerability and Clinical Outcomes
The most common adverse events possibly related to CAR T-cell infusions were headache, nausea/vomiting, and fever, typically resolving within 72 hours without intervention. No dose-limiting toxicities were observed. One patient (S008), who enrolled prior to disease progression, exhibited a mild decrease in tumor size and improved facial nerve palsy, which was sustained for 12 months. Two other patients (S005 and S014), who enrolled after tumor progression, experienced slow disease progression but survived 494 and 328 days after initial CAR T-cell infusion, respectively.
Correlative Studies and Immune Activation
CAR T cells were detected in the cerebrospinal fluid (CSF) of two out of three evaluable patients (S005 and S008) post-infusion. Analysis of CSF samples revealed elevations in chemokines and cytokines, including CCL2, CXCL10, GM-CSF, IFNγ, IL15, IL1α, IL6, and TNFα, suggesting local immune activation within the CNS. Targeted mass spectrometry of CSF and serum samples identified modulation of several immunoregulatory proteins, including BCL10, CXCL13, HAVCR2 (TIM-3), ICOSLG (ICOS ligand), PDCD1LG2 (PD-L2), TNFRSF14, and VCAM-1.
Implications and Future Directions
These preliminary findings suggest that repeated intraventricular delivery of B7-H3 CAR T cells is feasible and well-tolerated in children with DIPG. The detection of CAR T cells in the CSF and evidence of local immune activation support the potential of this approach to target DIPG tumors. Further studies are needed to evaluate the efficacy of B7-H3 CAR T-cell therapy in a larger cohort of patients and to identify biomarkers predictive of treatment response. The researchers plan to explore multi-antigen targeting strategies and additional genetic modifications to improve CAR T-cell persistence and effector function.
According to the authors, serial liquid disease monitoring of relevant immunomodulatory proteins and tumor antigens via targeted, immune-MRM mass spectrometry may serve as an early determinant of response or treatment failure, and potentially also be predictive of tumor evolution and optimal next therapy.
