DIPG-47. SEQUENTIAL INTRAVENOUS AND INTRACEREBROVENTRICULAR GD2-CAR T-CELL THERAPY FOR H3K27M-MUTATED DIFFUSE MIDLINE GLIOMAS

Michelle Monje(Howard Hughes Medical Institute), Jasia Mahdi(Stanford University), Robbie G. Majzner(Stanford University), Kristen W. Yeom(Stanford University), Liora M. Schultz(Stanford University), Rebecca M. Richards(Stanford University), Valentin Barsan(Stanford University), Kun-Wei Song(Stanford University), Jennifer L. Kamens(Stanford University), Christina Baggott(Stanford University), Michael Kunicki(Stanford University), Alexandria Sung Lim(Stanford University), Agnes Reschke(Stanford University), Sharon Mavroukakis(Stanford University), Emily Egeler(Stanford University), Jennifer Moon(Stanford University), Shabnum Patel(Stanford University), Harshini Chinnasamy(Stanford University), Courtney Erickson(Stanford University), Ashley Jacobs(Stanford University), Allison K. Duh(Stanford University), Skyler P. Rietberg(Stanford University), Ramya Tunuguntla(Stanford University), Dorota D. Klysz(Stanford University), Carley Fowler(Stanford University), Sean Green(Stanford University), Barbara Beebe(Stanford University), Casey Carr(Stanford University), Michelle Fujimoto(Stanford University), Annie Kathleen Brown(Stanford University), Ann-Louise G Peterson(Stanford University), Catherine McIntyre(Stanford University), Aman Siddiqui(Stanford University), Nadia Lepori‐Bui(Stanford University), Katlin Villar(Stanford University), Kymhuynh Pham(Stanford University), Rachel Bove(Stanford University), Eric Musa(Stanford University), Warren D. Reynolds(Stanford University), Adam Kuo(Stanford University), Snehit Prabhu(Stanford University), Lindsey Rasmussen(Stanford University), Timothy T. Cornell(Stanford University), Soni Partap(Stanford University), Paul G. Fisher(Stanford University), Cynthia Campen(Stanford University), Gerald A. Grant(Stanford University), Laura M. Prolo(Stanford University), Xiaobu Ye(Johns Hopkins University), Bita Sahaf(Stanford University), Kara L. Davis(Stanford University), Steven A. Feldman(Stanford University), Sneha Ramakrishna(Stanford University), Crystal L. Mackall(Stanford University)
Neuro-Oncology
June 18, 2024
10.1093/neuonc/noae064.100
Cited by 0Open Access
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Abstract

Abstract 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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