DIPG-47. SEQUENTIAL INTRAVENOUS AND INTRACEREBROVENTRICULAR GD2-CAR T-CELL THERAPY FOR H3K27M-MUTATED DIFFUSE MIDLINE GLIOMAS
Neuro-oncology(2024)
摘要
BACKGROUND H3K27M-mutant diffuse midline gliomas (DMGs) express uniformly high levels of the GD2 disialoganglioside. In preclinical models, chimeric antigen receptor modified T-cells (CAR T-cells) targeting GD2 robustly regressed orthotopically xenografted DMGs. METHODS This Phase I trial (NCT04196413) administered one IV dose of autologous T-cells transduced with a GD2-CAR retroviral vector to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline gliomas at two dose levels (DL1=1e6 GD2-CAR T-cells/kg; DL2=3e6 GD2-CAR T-cells/kg) following standard lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit following IV infusion were eligible for subsequent intracerebroventricular (ICV) GD2-CAR T-cell infusions (10-30e6 GD2-CAR T-cells). Primary objectives were to determine feasibility of manufacturing, assess tolerability of IV GD2-CAR T-cells in patients with DIPG and sDMG, and identify a maximally tolerated dose of IV GD2-CAR T-cells following lymphodepleting chemotherapy. Secondary objectives included preliminary assessments of benefit. Here we report the final results of Arm A. RESULTS Thirteen patients enrolled and 11 received one IV GD2-CAR T infusion on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CAR T-cells were successfully manufactured for each patient. After IV infusion, no dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric reductions of 52%, 54%, 91% and 100%. One patient exhibited a complete response durable for >30 months since therapy began. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. CONCLUSIONS Sequential IV followed by ICV GD2-CAR T-cells infusions induced tumor regressions and neurological improvements. DL1 was established as the maximally tolerated IV GD2-CAR T-cell dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.
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