EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses.

Autor:	Lertsumitkul L; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia., Iliopoulos M; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia., Wang SS; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia., McArthur SJ; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia., Ebert LM; Translational Oncology, Centre for Cancer Biology, Adelaide, South Australia, Australia.; The University of Adelaide Adelaide Medical School, Adelaide, South Australia, Australia.; Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia., Davenport AJ; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia., Endersby R; Brain Tumour Research Program, Telethon Kids Institute, Perth, Western Australia, Australia., Hansford JR; Michael Rice Children's Hematology and Oncology Center, Women's and Children's Hospital; South Australia Health and Medical Research Institute; South Australia ImmmunoGenomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia., Drummond KJ; Department of Neurosurgery, Royal Melbourne Hospital Department of Surgery, Parkville, Victoria, Australia.; Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia., Cross R; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia., Jenkins MR; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia jenkins.m@wehi.edu.au.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Department of Biochemistry and Chemistry, La Trobe University, Melbourne, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Aug 07; Vol. 12 (8). Date of Electronic Publication: 2024 Aug 07.
DOI:	10.1136/jitc-2024-009486
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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