Journal Article

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

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

2022

Overview

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

• Publisher: Nature Publishing Group,Nature Publishing Group UK
• Subject: Antigens / Astrocytoma - genetics / Astrocytoma - immunology / Astrocytoma - pathology / Astrocytoma - therapy / Brain stem / Brain Stem Neoplasms - genetics / Brain Stem Neoplasms - immunology / Brain Stem Neoplasms - pathology / Brain Stem Neoplasms - therapy / Cell therapy / Cerebrospinal fluid / Child / Chimeric antigen receptors / Cytokines / Dosage / Dysarthria / Fever / Gait / Gangliosides - immunology / Gene Expression Profiling / Glioma - genetics / Glioma - immunology / Glioma - pathology / Glioma - therapy / Glioma cells / Hearing impairment / Heterogeneity / Histones - genetics / Humans / Hydrocephalus / Immunotherapy, Adoptive - methods / Inflammation / Intracranial pressure / Lymphocytes / Lymphocytes T / Mutation / Neurological disorders / Neurology / Patients / Receptors, Chimeric Antigen - immunology / Spinal cord / Spinal Cord Neoplasms - genetics / Spinal Cord Neoplasms - immunology / Spinal Cord Neoplasms - pathology / Spinal Cord Neoplasms - therapy / Steroids / Toxicity / Transcriptomics / Tumors