GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas

Robbie G. Majzner, Sneha Ramakrishna, Kristen W. Yeom, Shabnum Patel, Harshini Chinnasamy, Liora M. Schultz, Rebecca M. Richards, Li Jiang, Valentin Barsan, Rebecca Mancusi, Anna C. Geraghty, Zinaida Good, Aaron Y. Mochizuki, Shawn M. Gillespie, Angus Martin Shaw Toland, Jasia Mahdi, Agnes Reschke, Esther H. Nie, Isabelle J. Chau, Maria Caterina Rotiroti, Christopher W. Mount, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Courtney Erickson, Sean Green, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Warren Reynolds, Sreevidya Kurra, Katherine E. Warren, Snehit Prabhu, Hannes Vogel, Lindsey Rasmussen, Timothy T. Cornell, Sonia Partap, Paul G. Fisher, Cynthia J. Campen, Mariella G. Filbin, Gerald Grant, Bita Sahaf, Kara L. Davis, Steven A. Feldman, Crystal L. Mackall () and Michelle Monje ()
Additional contact information
Robbie G. Majzner: Stanford University
Sneha Ramakrishna: Stanford University
Kristen W. Yeom: Stanford University
Shabnum Patel: Stanford University
Harshini Chinnasamy: Stanford University
Liora M. Schultz: Stanford University
Rebecca M. Richards: Stanford University
Li Jiang: Division of Pediatric Neuro-Oncology, Dana Farber Cancer Institute
Valentin Barsan: Stanford University
Rebecca Mancusi: Stanford University
Anna C. Geraghty: Stanford University
Zinaida Good: Stanford University
Aaron Y. Mochizuki: Stanford University
Shawn M. Gillespie: Stanford University
Angus Martin Shaw Toland: Stanford University
Jasia Mahdi: Stanford University
Agnes Reschke: Stanford University
Esther H. Nie: Stanford University
Isabelle J. Chau: Stanford University
Maria Caterina Rotiroti: Stanford University
Christopher W. Mount: Stanford University
Christina Baggott: Stanford University
Sharon Mavroukakis: Stanford University
Emily Egeler: Stanford University
Jennifer Moon: Stanford University
Courtney Erickson: Stanford University
Sean Green: Stanford University
Michael Kunicki: Stanford University
Michelle Fujimoto: Stanford University
Zach Ehlinger: Stanford University
Warren Reynolds: Stanford University
Sreevidya Kurra: Stanford University
Katherine E. Warren: Division of Pediatric Neuro-Oncology, Dana Farber Cancer Institute
Snehit Prabhu: Stanford University
Hannes Vogel: 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
Mariella G. Filbin: Division of Pediatric Neuro-Oncology, Dana Farber Cancer Institute
Gerald Grant: Stanford University
Bita Sahaf: Stanford University
Kara L. Davis: Stanford University
Steven A. Feldman: Stanford University
Crystal L. Mackall: Stanford University
Michelle Monje: Stanford University

Nature, 2022, vol. 603, issue 7903, 934-941

Abstract: Abstract Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Date: 2022
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DOI: 10.1038/s41586-022-04489-4

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