Dragon, Anna Christina and Thoelke, Stefanie and Mausberg, Philip and Zimmermann, Katharina and Blasczyk, Rainer and Hudecek, Michael and Abken, Hinrich and Schambach, Axel and Maecker-Kolhoff, Britta and Eiz-Vesper, Britta (2025) LMP2A-Targeting CAR-T Cells Equipped With Inducible IL-18 to Address EBV-Associated Malignancies. HLA, 106 (4): e70439. ISSN 2059-2302, 2059-2310
Full text not available from this repository. (Request a copy)Abstract
Epstein-Barr virus (EBV) infects up to 95% of the world's population and persists in B cells and epithelial cells. Uncontrolled proliferation of EBV-infected cells can result in the development of EBV-associated malignancies, for example, post-transplant lymphoproliferative disorder (PTLD) or nasopharyngeal cancer (NPC). It is estimated that 1.8% of deaths due to cancer worldwide are associated with EBV, and the treatment options are limited. As a new therapeutic approach, we developed chimeric antigen receptor T cells targeting EBV-derived latent membrane protein 2A (LMP2A_CAR-Ts). To enable specific elimination of malignant B cells infected with the intracellular pathogen, we utilised T-cell receptor (TCR)-like specificity to generate a CAR against the LMP2A-derived peptide CLGGLLTMV (CLG) presented in the context of HLA-A*02:01. To increase functionality in the tumour microenvironment, LMP2A_CAR-Ts were additionally equipped with inducible release of IL-12 (LMP2A_iIL-12_TRUCKs) or IL-18 (LMP2A_iIL-18_TRUCKs). LMP2A_CAR-Ts and LMP2A_iIL-18_TRUCKs specifically recognised HLA-A*02:01(+) EBV-transformed B-lymphoblastoid cell lines and HLA-A*02:01(+) cells loaded with CLG peptide (A02_CLG(+) cells), proving their target specificity, while, unexpectedly, LMP2A_iIL-12_TRUCKs exhibited a disparate T-EM and NK-like phenotype and A02_CLG-independent reactivity. In contrast, LMP2A_CAR-Ts and LMP2A_iIL-18_TRUCKs effectively induced T-cell signalling, activation, release of cytotoxic mediators, including IL-18 by LMP2A_iIL-18_TRUCKs and mediated cytotoxicity in a target-specific manner. Our results demonstrate that LMP2A_CAR-Ts and LMP2A_iIL-18_TRUCKs specifically recognise the EBV-derived CLG peptide presented in the context of HLA-A*02:01. Especially, LMP2A_iIL-18_TRUCKs with an even improved anti-tumour response, as well as the potential to recruit bystander immune cells and overcome EBV-mediated immune evasion strategies, might serve as a novel treatment option for various EBV-associated malignancies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EPSTEIN-BARR-VIRUS; ACTIVATION; THERAPY; DISEASE; CAR-T cells; EBV-associated malignancies; inducible cytokine expression; LMP2A; PTLD; TCR-like antibody; TCR-like CAR; TRUCKs |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jul 2026 09:27 |
| Last Modified: | 28 Jul 2026 09:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67305 |
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