CTIM-15. LOCOREGIONAL ADMINISTRATION OF B7-H3-CAR T CELLS EXPRESSING 41BB LIGAND FOR PEDIATRIC PATIENTS WITH PRIMARY CNS TUMORS: PRELIMINARY RESULTS FROM A PHASE I STUDY

Abstract Outcomes for pediatric patients with diffuse midline glioma (DMG) and relapsed/refractory CNS malignancies remain poor. Loc3CAR is an ongoing, first-in-human, phase I clinical trial (NCT05835687) evaluating intracranial delivery of B7-H3-CAR T cells expressing 41BB ligand (B7-H3-CAR-T) for patients ≤21 years old with i) relapsed/refractory B7-H3+ CNS tumors (Cohort A), or ii) DMG post-radiation (Cohort B). Treatment included 6 intracerebroventricular B7-H3-CAR-T infusions administered over 7 weeks. Primary and secondary outcomes were safety and disease response, respectively. To date, 84% (21/25) of tumors screened were B7-H3+ (median H-score 200; range 0-300). CAR-T products were successfully manufactured for all patients enrolled on the collection/manufacture phase of the trial (n=11). Eight patients (7 cohort A; 1 cohort B) were treated with a total of 42 infusions on dose level 1 (1x107/3x107 CAR+ T cells/dose). Post-infusion, multiple participants exhibited neurologic findings suggestive of on-tumor CAR-T activation, including seizure, dysphasia, and localized pain. One patient, with a large tumor burden and high B7-H3 expression (H-score = 300), experienced a dose limiting toxicity with unresponsiveness and decorticate posturing approximately 16 hours post-infusion #1. Their clinical status rapidly improved following CSF removal and intravenous dexamethasone. Common adverse events attributable to B7-H3-CAR-T included headache (8/8), fever (7/8), and nausea/vomiting (5/8). Two of 7 (29%) evaluable patients achieved clinical benefit with stable disease at week 8. B7-H3-CAR-T and inflammatory cytokines were detected in the CSF from all patients evaluated. Circulating tumor DNA (ctDNA) was measured using a novel DNA methylation-based sequencing pipeline and detected in the CSF from 6/8 patients. For 2 patients, ctDNA abundance increased post-infusion, followed by clearance, suggesting subclinical antitumor activity. Single cell RNAseq of immune cells in the CSF from 1 patient analyzed to date, demonstrated abundant Tregs post-infusion #4, suggesting B7-H3-CAR-T may induce local anti-inflammatory responses. Overall, intracranially administered B7-H3-CAR-T have an acceptable safety profile and warrant continued exploration for pediatric patients with CNS tumors.