Next-generation LMP2A-targeting TCR-recombinant T cells with inducible IL-18 expression to treat EBV-associated malignancies.

Epstein-Barr virus (EBV) infects more than 90% of the population and establishes a lifelong persistence in memory B cells, passing through several latency stages (I-III). In immunocompromised patients, EBV infections and reactivations can lead to severe complications, such as post-transplant lymphoproliferative disorder (PTLD), a malignant B cell lymphoproliferation. The EBV latent membrane protein 2A (LMP2A) induces activation and proliferation of infected B cells and is expressed in latency stages II/III, that are associated with several EBV malignancies. Here, T cell receptor (TCR)-engineered T cells based on a TCR recognizing the clinically relevant HLA-A∗02:01-restricted LMP2A-derived peptide CLGGLLTMV (A∗02_LMP2ACLG) and equipped with a TCR-inducible cassette for IL-18 release (iIL-18_LMP2A_TCR-T cells) aiming to prevent exhaustion and promote remodeling of the immunosuppressive tumor microenvironment (TME) were developed. The iIL-18_LMP2A_TCR-T cells exhibited improved cytotoxicity against HLA-A∗02:01+ EBV-infected B-lymphoblastoid cell lines (EBV+ B-LCLA∗02:01) serving as in vitro PTLD model, when compared to LMP2A_TCR-T cells without iIL-18. The superior functionality of iIL-18_LMP2A_TCR-T cells was further confirmed in multicellular tumor spheroid (MCTS) models, where they mediated sustained control of EBV+ B-LCLA∗02:01 growth, highlighting their potential as an effective therapeutic approach for the immune-mediated eradication of EBV-associated malignancies, including PTLD.