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

Publication ,  Journal Article
Majzner, RG; Ramakrishna, S; Yeom, KW; Patel, S; Chinnasamy, H; Schultz, LM; Richards, RM; Jiang, L; Barsan, V; Mancusi, R; Geraghty, AC ...
Published in: Nature
March 2022

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.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

March 2022

Volume

603

Issue

7903

Start / End Page

934 / 941

Location

England

Related Subject Headings

  • Spinal Cord Neoplasms
  • Receptors, Chimeric Antigen
  • Mutation
  • Immunotherapy, Adoptive
  • Humans
  • Histones
  • Glioma
  • General Science & Technology
  • Gene Expression Profiling
  • Gangliosides
 

Citation

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Majzner, R. G., Ramakrishna, S., Yeom, K. W., Patel, S., Chinnasamy, H., Schultz, L. M., … Monje, M. (2022). GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature, 603(7903), 934–941. https://doi.org/10.1038/s41586-022-04489-4
Majzner, Robbie G., Sneha Ramakrishna, Kristen W. Yeom, Shabnum Patel, Harshini Chinnasamy, Liora M. Schultz, Rebecca M. Richards, et al. “GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.Nature 603, no. 7903 (March 2022): 934–41. https://doi.org/10.1038/s41586-022-04489-4.
Majzner RG, Ramakrishna S, Yeom KW, Patel S, Chinnasamy H, Schultz LM, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. 2022 Mar;603(7903):934–41.
Majzner, Robbie G., et al. “GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.Nature, vol. 603, no. 7903, Mar. 2022, pp. 934–41. Pubmed, doi:10.1038/s41586-022-04489-4.
Majzner RG, Ramakrishna S, Yeom KW, Patel S, Chinnasamy H, Schultz LM, Richards RM, Jiang L, Barsan V, Mancusi R, Geraghty AC, Good Z, Mochizuki AY, Gillespie SM, Toland AMS, Mahdi J, Reschke A, Nie EH, Chau IJ, Rotiroti MC, Mount CW, Baggott C, Mavroukakis S, Egeler E, Moon J, Erickson C, Green S, Kunicki M, Fujimoto M, Ehlinger Z, Reynolds W, Kurra S, Warren KE, Prabhu S, Vogel H, Rasmussen L, Cornell TT, Partap S, Fisher PG, Campen CJ, Filbin MG, Grant G, Sahaf B, Davis KL, Feldman SA, Mackall CL, Monje M. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. 2022 Mar;603(7903):934–941.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

March 2022

Volume

603

Issue

7903

Start / End Page

934 / 941

Location

England

Related Subject Headings

  • Spinal Cord Neoplasms
  • Receptors, Chimeric Antigen
  • Mutation
  • Immunotherapy, Adoptive
  • Humans
  • Histones
  • Glioma
  • General Science & Technology
  • Gene Expression Profiling
  • Gangliosides