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CAR-armed cell therapy for gliomas.

ABSTRACT: Chimeric antigen receptor (CAR)-armed cell therapy has developed rapidly in recent years, especially in the treatment of leukemia. However, the treatment methods for solid tumors represented by glioma have not achieved the ideal therapeutic effect. This situation necessitates learning from chimeric antigen receptor T cell (CAR-T) treatment in other malignancies and discovering the differences between gliomas and other solid tumors. The current design idea is to enhance the targeting, regulatory effects, and adaptation of CAR-armed cells. This review traced not only clinical trials, but also several animal experiments, which might promote the development of CAR-T treatment in glioma. Furthermore, we have discussed the obstacles to CAR-T in the treatment of glioma and the current possible solutions.

SUBMITTER: Zhai Y

PROVIDER: S-EPMC6943349 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CAR-armed cell therapy for gliomas.

Zhai You Y Li Guanzhang G Jiang Tao T Zhang Wei W

American journal of cancer research 20191201 12

Chimeric antigen receptor (CAR)-armed cell therapy has developed rapidly in recent years, especially in the treatment of leukemia. However, the treatment methods for solid tumors represented by glioma have not achieved the ideal therapeutic effect. This situation necessitates learning from chimeric antigen receptor T cell (CAR-T) treatment in other malignancies and discovering the differences between gliomas and other solid tumors. The current design idea is to enhance the targeting, regulatory ...[more]

PMID: 31911846

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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.

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CAR-armed cell therapy for gliomas.

Publications

CAR-armed cell therapy for gliomas.

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