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

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.

SUBMITTER: Majzner RG

PROVIDER: S-EPMC8967714 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

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

Nature 20220207 7903

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system<sup>1</sup>. 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<sup>2</sup>, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Becaus ...[more]

PMID: 35130560

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Project description:Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system (CNS) tumors that occur most commonly in children and young adults1. Average life expectancy is ten months from diagnosis, and 5-year survival is less than 1%2. Palliative radiotherapy is the only established treatment3, and neither cytotoxic nor targeted pharmacological approaches have demonstrated anti-tumor responses or improved prognosis to date3,4. We previously discovered that the disialoganglioside GD2 is highly and uniformly expressed on H3K27M+ DMG cells and demonstrated that intravenously (IV) administered GD2.4-1BB.z chimeric antigen receptor (CAR) T-cells eradicated established DMGs in patient-derived orthotopic murine models5, thereby providing the rationale for a first-in-human/first-in-child Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced inflammation and edema of the brainstem can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, a number of neurocritical care precautions were incorporated in the clinical trial design and management plan. Here we present the clinical experience from the first four patients with H3K27M+ DMG treated with GD2-CAR T-cells at dose level 1 (DL1; 1e6 GD2-CAR T-cells/kg administered IV). Patients who exhibited clinical benefit were eligible for subsequent administrations of GD2-CAR T-cells. Given preclinical evidence for increased CAR T-cell potency6, and the potential for diminished immunogenicity with locoregional administration, second doses were administered intracerebroventricularly (ICV) through an Ommaya catheter to three patients. As predicted from preclinical models, toxicity was largely related to the neuroanatomical location of the tumors and was reversible with intensive supportive care. Although GD2 is expressed at low levels in normal neural tissue, no evidence of on-target, off-tumor toxicity was observed. Three of four patients exhibited clinical and radiographic improvement, underscoring the promise of this approach for H3K27M+ DMG therapy. Correlative studies of serum and CSF revealed marked proinflammatory cytokine production following GD2 CAR T cell administration and single cell transcriptomic analysis of 65,598 single cells from CAR T cell products and patient CSF has begun to reveal differences that correlate with the heterogeneity between subjects and routes of administration.

Dataset Information

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

Publications

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

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