ID #174 Pioneering quad-targeting CAR T cell therapy in pediatric CNS tumors – analysis from the completed first-in-human phase 1 trial BrainChild-04
Rebecca Ronsley, Marlena Bannick, Prabha Narayanaswamy, Stephanie Rawlings-Rhea, Wenjun Huanb, Adam Beebe, Christopher Brown, Daniel Runco, Erin Crotty, Sarah Leary, Joelle Straehla, Amy Lee, Susan Holtzclaw, Corinne Hoeppner, Amy Beckstrom, Corinne Summers, Colleen Annesley, Julie Park, Michael Jensen, Nicholas VitanzaAbstract
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.