Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas

Michelle Monje (), Jasia Mahdi, Robbie Majzner, Kristen W. Yeom, Liora M. Schultz, Rebecca M. Richards, Valentin Barsan, Kun-Wei Song, Jen Kamens, Christina Baggott, Michael Kunicki, Skyler P. Rietberg, Alexandria Sung Lim, Agnes Reschke, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Shabnum Patel, Harshini Chinnasamy, Courtney Erickson, Ashley Jacobs, Allison K. Duh, Ramya Tunuguntla, Dorota Danuta Klysz, Carley Fowler, Sean Green, Barbara Beebe, Casey Carr, Michelle Fujimoto, Annie Kathleen Brown, Ann-Louise G. Petersen, Catherine McIntyre, Aman Siddiqui, Nadia Lepori-Bui, Katlin Villar, Kymhuynh Pham, Rachel Bove, Eric Musa, Warren D. Reynolds, Adam Kuo, Snehit Prabhu, Lindsey Rasmussen, Timothy T. Cornell, Sonia Partap, Paul G. Fisher, Cynthia J. Campen, Gerald Grant, Laura Prolo, Xiaobu Ye, Bita Sahaf, Kara L. Davis, Steven A. Feldman, Sneha Ramakrishna () and Crystal Mackall ()
Additional contact information
Michelle Monje: Stanford University
Jasia Mahdi: Stanford University
Robbie 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
Jen Kamens: Stanford University
Christina Baggott: Stanford University
Michael Kunicki: Stanford University
Skyler P. Rietberg: 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
Ramya Tunuguntla: Stanford University
Dorota Danuta 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 Health Care
Aman Siddiqui: Stanford Health Care
Nadia Lepori-Bui: Stanford Health Care
Katlin Villar: Stanford Health Care
Kymhuynh Pham: Stanford Health Care
Rachel Bove: Stanford Health Care
Eric Musa: Stanford Health Care
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 J. Campen: Stanford University
Gerald Grant: Stanford University
Laura Prolo: Stanford University
Xiaobu Ye: Johns Hopkins School of Medicine
Bita Sahaf: Stanford University
Kara L. Davis: Stanford University
Steven A. Feldman: Stanford University
Sneha Ramakrishna: Stanford University
Crystal Mackall: Stanford University

Nature, 2025, vol. 637, issue 8046, 708-715

Abstract: Abstract H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models1. Arm A of Phase I trial no. NCT04196413 (ref. 2) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg−1; DL2, 3 × 106 kg−1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 106 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.

Date: 2025
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DOI: 10.1038/s41586-024-08171-9

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