EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses
- Author(s)
- Lertsumitkul, L; Iliopoulos, M; Wang, SS; McArthur, SJ; Ebert, LM; Davenport, AJ; Endersby, R; Hansford, JR; Drummond, KJ; Cross, R; Jenkins, MR;
- Details
- Publication Year 2024-08-07,Volume 12,Issue #8,Page e009486
- Journal Title
- Journal for Immunotherapy of Cancer
- Abstract
- BACKGROUND: High-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. METHODS: We 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. RESULTS: EphA3-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. CONCLUSION: Building 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
- Keywords
- Humans; Animals; *Receptor, EphA3; Mice; *Receptors, Chimeric Antigen/immunology/metabolism; *Glioma/therapy/immunology; T-Lymphocytes/immunology/metabolism; Brain Neoplasms/immunology/therapy; Xenograft Model Antitumor Assays; Immunotherapy, Adoptive/methods; Cell Line, Tumor; Female; Immunologic Memory; Chimeric antigen receptor - CAR; Immunotherapy
- Research Division(s)
- Immunology
- PubMed ID
- 39111833
- Publisher's Version
- https://doi.org/10.1136/jitc-2024-009486
- Open Access at Publisher's Site
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Creation Date: 2024-08-14 09:49:39
Last Modified: 2024-08-14 11:20:40