Abstract Background BrainChild-04 is a first-in-human trial evaluating four antigen-targeting CAR (quad-CAR) T cells for children with CNS tumors. The trial administered locoregional CAR T cells with multi-antigen targeting to address high-grade CNS tumor heterogeneity. Methods Primary and secondary endpoints included feasibility and safety, disease response, and CAR T cell activity. Quad-CAR T cells were manufactured from CD4+ and CD8+ T cells transduced with pooled B7-H3, IL13zetakine, EGFR806, or HER2 CAR lentiviral vectors. Three dose regimens were evaluated with maximum of 100 million CAR-T cells/dose. Two arms received weekly intracranial infusions for 3 weeks of a 4-week cycle: Arm A enrolled patients with DIPG, while Arm B enrolled patients with non-pontine DMG or other CNS tumors. Results 48 patients enrolled (DIPG (n = 26), non-pontine DMG (n = 12), other CNS tumors (n = 10)). Manufacturing was successful for all patients (94% in one attempt); 39 patients received infusion and 9 did not due to rapid disease progression. 291 total CAR T doses were delivered to 21 patients on Arm A and 18 patients on Arm B. The most frequent adverse events were grade 1-3 fever (n = 37/39), nausea/vomiting (n = 37/39), fatigue (n = 37/39), and grade 2-3 headache (n = 34/39). There were no related grade 4 toxicities. One dose-limiting toxicity occurred (grade 3 acoustic nerve disorder). TIAN grade 1-3 was retrospectively identified in 30/39 patients. No CRS or ICANS was observed. For Arm A and Arm B respectively, median survival from initial CAR T infusion was 8.55 and 9 months, and from diagnosis was 15.6 and 27.4 months. CSF proteomics quantified 85 proteins and showed temporal changes in chemokines and CAR T antigens (eg.B7H3). Correlation with disease progression and AE analyses will be presented. Conclusions Locoregional delivery of quad-CAR T cells was feasible and tolerable. Results support continued investigation to assess anti-tumor activity in CNS tumors.
Ronsley et al. (Tue,) studied this question.