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

dc.contributor.author

Majzner, Robbie G

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Ramakrishna, Sneha

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Yeom, Kristen W

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Patel, Shabnum

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Chinnasamy, Harshini

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Schultz, Liora M

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Richards, Rebecca M

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Jiang, Li

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Barsan, Valentin

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Mancusi, Rebecca

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Geraghty, Anna C

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Good, Zinaida

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Mochizuki, Aaron Y

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Gillespie, Shawn M

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Toland, Angus Martin Shaw

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Mahdi, Jasia

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Reschke, Agnes

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Nie, Esther H

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Chau, Isabelle J

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Rotiroti, Maria Caterina

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Mount, Christopher W

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Baggott, Christina

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Mavroukakis, Sharon

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Egeler, Emily

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Moon, Jennifer

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Erickson, Courtney

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Green, Sean

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Kunicki, Michael

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Fujimoto, Michelle

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Ehlinger, Zach

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Reynolds, Warren

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Kurra, Sreevidya

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Warren, Katherine E

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Prabhu, Snehit

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Vogel, Hannes

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Rasmussen, Lindsey

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Cornell, Timothy T

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Partap, Sonia

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Fisher, Paul G

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Campen, Cynthia J

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Filbin, Mariella G

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Grant, Gerald

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Sahaf, Bita

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Davis, Kara L

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Feldman, Steven A

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Mackall, Crystal L

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Monje, Michelle

dc.date.accessioned

2022-09-30T14:18:58Z

dc.date.available

2022-09-30T14:18:58Z

dc.date.issued

2022-03

dc.date.updated

2022-09-30T14:18:36Z

dc.description.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.

dc.identifier

10.1038/s41586-022-04489-4

dc.identifier.issn

0028-0836

dc.identifier.issn

1476-4687

dc.identifier.uri

https://hdl.handle.net/10161/25878

dc.language

eng

dc.publisher

Springer Science and Business Media LLC

dc.relation.ispartof

Nature

dc.relation.isversionof

10.1038/s41586-022-04489-4

dc.subject

Humans

dc.subject

Glioma

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Astrocytoma

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Brain Stem Neoplasms

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Spinal Cord Neoplasms

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Gangliosides

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Histones

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Immunotherapy, Adoptive

dc.subject

Gene Expression Profiling

dc.subject

Mutation

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Child

dc.subject

Receptors, Chimeric Antigen

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Grant, Gerald|0000-0002-2651-4603

pubs.begin-page

934

pubs.end-page

941

pubs.issue

7903

pubs.organisational-group

Duke

pubs.organisational-group

School of Medicine

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Duke Cancer Institute

pubs.organisational-group

Neurosurgery

pubs.publication-status

Published

pubs.volume

603

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