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EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses
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EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses
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Journal Article
EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses
2024
Overview
BackgroundHigh-grade gliomas including glioblastoma (GBM) and diffuse midline gliomas (DMG) represent the most lethal and aggressive brain cancers where current treatment modalities offer limited efficacy. Chimeric antigen receptor (CAR) T cell therapies have emerged as a promising strategy, boasting tumor-specific targeting and the unique ability to penetrate the blood-brain barrier. However, the effective clinical application hinges on the optimal choice of antigen, with a limited number, currently under investigation.MethodsWe employed cell surface proteomic analysis of primary human high-grade glioma samples from both adult and pediatric patients. This led to the identification of Ephrin type-A receptor 3 (EphA3) as a prevalently expressed target. We engineered a second-generation EphA3-targeted CAR T cell and assessed function using in vitro and in vivo models of GBM and DMG.ResultsEphA3-targeted CAR T cells demonstrated robust antigen-specific killing of human GBM and DMG cell lines in vitro. In an orthotopic xenograft NSG mouse model, EphA3-targeted CAR T cells not only effectively eradicated tumors but also established a functional T cell population protective on rechallenge. Remarkably, mice rechallenged with a second contralateral orthotopic tumor implantation achieved complete tumor clearance and maintained a sustained complete response 6 months following initial treatment.ConclusionBuilding on the proven safety profile of EphA3 antibodies in clinical settings, our study provides compelling preclinical evidence supporting the efficacy of EphA3-targeted CAR T cells against high-grade gliomas. These findings underscore the potential for transitioning this innovative therapy into clinical trials, aiming to revolutionize the treatment landscape for patients afflicted with these formidable brain cancers.
Publisher
BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
Subject
/ Animals
/ Antigens
/ Brain Neoplasms - immunology
/ Cells
/ Chimeric antigen receptor - CAR
/ Female
/ Glioma
/ Humans
/ Immune Cell Therapies and Immune Cell Engineering
/ Immunotherapy, Adoptive - methods
/ Kinases
/ Melanoma
/ Mice
/ Mutation
/ Patients
/ Proteins
/ Receptors, Chimeric Antigen - immunology
/ Receptors, Chimeric Antigen - metabolism
/ Tumors
