Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas

Michelle Monje(Stanford University), Jasia Mahdi(Stanford University), Robbie G. Majzner(Stanford University), Kristen W. Yeom(Stanford Medicine), Liora M. Schultz(Stanford University), Rebecca M. Richards(Stanford University), Valentin Barsan(Stanford University), Kun-Wei Song(Stanford University), Jen 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. Petersen(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), Sonia Partap(Stanford University), Paul G. Fisher(Stanford University), Cynthia Campen(Stanford University), Gerald A. Grant(Stanford University), Laura M. Prolo(Stanford Medicine), Xiaobu Ye, Bita Sahaf(Stanford University), Kara L. Davis(Stanford University), Steven A. Feldman(Stanford University), Sneha Ramakrishna(Stanford University), Crystal L. Mackall(Stanford University)
medRxiv
June 27, 2024
10.1101/2024.06.25.24309146
Cited by 7Open Access
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Abstract

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. 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 tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.

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