Phase I study of anti-GD2 Chimeric Antigen Receptor-Expressing T cells in pediatric and young adult patients affected by relapsed/refractory central nervous system tumors: preliminary data

Introduction: Despite the use of aggressive multimodal treatments, childhood central nervous system (CNS) tumors remain a major cause of morbidity and mortality among pediatric patients. Chimeric antigen receptor (CAR) T-cell therapies have emerged as promising options. Here, we present preliminary data of a Phase 1 clinical trial to evaluate GD2-targeting CAR T-cells (GD2-CART01) for treating recurrent or refractory CNS tumors in pediatric and young adult patients. Materials and methods: This trial is designed to stratify patients into three arms based on tumor histology and location to sequentially evaluate safety: ARM A (medulloblastoma and other embryonal tumors), ARM B (hemispheric high-grade gliomas), and ARM C (thalamic HGG, diffuse midline glioma, DIPG, and other rare CNS tumors). Each arm follows a 3+3 dose escalation/de-escalation schema across five dose levels (DL): DL1 (0.25 x 10^6 cells/kg), DL2 (0.5 x 10^6 cells/kg), DL3 (1.0 x 10^6 cells/kg), DL4 (3.0 x 10^6 cells/kg), and DL5 (6.0 x 10^6 cells/kg). The treatment plan will include: T-cell apheresis, retroviral production, T-cell production and transduction, lymphodepleting regimen and iC9-GD2-CAR-T cell infusion. Patients will be monitored clinically, with laboratory tests, and by detecting CAR and cytokines in cerebrospinal fluid (CSF) and blood. Brain and spine magnetic resonance imaging (MRI) and CSF cytology will be used to assess disease response. Results: Between November 2023 and October 2024, 12 patients were enrolled, with 8 receiving treatment. GD2-CART01 was manufactured successfully in all the patients. All treated patients demonstrated CAR T-cell expansion, peaking around two weeks post-infusion. There was no significant difference in CAR T expansion and cytokine levels between the two different dose levels tested, nor between arms of treatment. However, it appears that the patients in arm B had greater CAR T expansion and cytokine expression. No dose-limiting toxic effects were reported in patients treated to date. Mild cytokine release syndrome occurred in 87.5% of cases, correlating with elevated cytokine levels in both PB and CSF. Two patients (25%) experienced Immune effector cell-associated neurotoxicity syndrome. Tumor inflammation associated neurotoxicity was reported in two cases (25%). All patients underwent intracranial pressure (ICP) telemetric monitoring, and none experienced complications related to intracranial hypertension. Hematologic toxic effects developed in all the patients. All side effects were reversible. Regarding patient outcomes at six week post infusion, we documented one partial response, three disease progression, one case of pseudoprogression, and one stable disease. Conclusions: Our initial findings suggest that GD2 CAR T-cell therapy is safe. In terms of kinetics, we observed CAR T-cell expansion and cytokine increases in all cases. However, a single systemic infusion may not suffice to control the disease, highlighting the need to explore additional intraventricular infusions. Patient selection also appears crucial, as lower tumor burden may enhance treatment efficacy.