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Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas
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Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas
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Journal Article
Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas
2025
Overview
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 models
1
. 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 × 10
6
kg
−
1
; DL2, 3 × 10
6
kg
−1
) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10
6
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.
We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M
+
diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adult
/ Antigens
/ Brain Neoplasms - immunology
/ Brain Stem Neoplasms - genetics
/ Brain Stem Neoplasms - pathology
/ Brain Stem Neoplasms - therapy
/ Female
/ Glioma
/ Humanities and Social Sciences
/ Humans
/ Immunotherapy, Adoptive - adverse effects
/ Immunotherapy, Adoptive - methods
/ Male
/ Mutants
/ Mutation
/ Patients
/ Receptors, Chimeric Antigen - genetics
/ Receptors, Chimeric Antigen - immunology
/ Receptors, Chimeric Antigen - metabolism
/ Science
/ Steroids
/ T-Lymphocytes - transplantation
/ Toxicity
/ Tumors
