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

脑脊液 医学 毒性 胶质瘤 癌症研究 脊髓 中枢神经系统 内科学 精神科
作者
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 Mochizuki,Shawn Gillespie,Angus 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,Zachary Ehlinger,Warren D. 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 A. Grant,Bita Sahaf,Kara L. Davis,Steven A. Feldman,Crystal L. Mackall,Michelle Monje
出处
期刊:Nature [Nature Portfolio]
卷期号:603 (7903): 934-941 被引量:533
标识
DOI:10.1038/s41586-022-04489-4
摘要

Abstract Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system 1 . 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 cells 2 , 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 × 10 6 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly 3 . 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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