{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:31:32Z","timestamp":1790962292043,"version":"4.1.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T00:00:00Z","timestamp":1679616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005946","name":"Jackson Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005946","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The ubiquitous Epstein\u2013Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. EBV is an immune-evasive pathogen that promotes CD8<jats:sup>+<\/jats:sup> T cell exhaustion and dysregulates CD4<jats:sup>+<\/jats:sup> T cell functions. Burkitt lymphoma (BL) is frequently associated with EBV infections. Since BL relapses after conventional therapies are difficult to treat, we evaluated prospective off-the-shelf edited CAR-T cell therapies targeting CD19 or the EBV gp350 cell surface antigen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used CRISPR\/Cas9 gene editing methods to knock in (KI) the CD19CAR.CD28z or gp350CAR.CD28z into the T cell receptor (TCR) alpha chain (<jats:italic>TRAC<\/jats:italic>) locus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Applying upscaled methods with the ExPERT ATx<jats:sup>\u00ae<\/jats:sup> MaxCyte system, KI efficacy was ~20% of the total ~2 \u00d7 10<jats:sup>8<\/jats:sup> TCR-knocked-out (KO) generated cells. <jats:sup>KO<\/jats:sup>TCR<jats:sup>KI<\/jats:sup>CAR-T cells were co-cultured <jats:italic>in vitro<\/jats:italic> with the gp350<jats:sup>+<\/jats:sup>CD19<jats:sup>+<\/jats:sup> BL cell lines Daudi (infected with type 1 EBV) or with Jiyoye (harboring a lytic type 2 EBV). Both types of CAR-T cells showed cytotoxic effects against the BL lines <jats:italic>in vitro<\/jats:italic>. CD8<jats:sup>+ KI<\/jats:sup>CAR-T cells showed higher persistency than CD4<jats:sup>+ KI<\/jats:sup>CAR-T cells after <jats:italic>in vitro<\/jats:italic> co-culture with BL and upregulation of the activation\/exhaustion markers PD-1, LAG-3, and TIM-3. Two preclinical <jats:italic>in vivo<\/jats:italic> xenograft models were set up with Nod.Rag.Gamma mice injected intravenously (i.v.) with 2 \u00d7 10<jats:sup>5<\/jats:sup> Daudi\/fLuc-GFP or with Jiyoye\/fLuc-GFP cells. Compared with the non-treated controls, mice challenged with BL and treated with CD19<jats:sup>KI<\/jats:sup>CAR-T cells showed delayed lymphoma dissemination with lower EBV DNA load. Notably, for the Jiyoye\/fLuc-GFP model, almost exclusively CD4<jats:sup>+<\/jats:sup> CD19<jats:sup>KI<\/jats:sup>CAR-T cells were detectable at the endpoint analyses in the bone marrow, with increased frequencies of regulatory T cells (T<jats:sub>regs<\/jats:sub>) and TIM-3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> T cells. Administration of gp350<jats:sup>KI<\/jats:sup>CAR-T cells to mice after Jiyoye\/GFP-fLuc challenge did not inhibit BL growth <jats:italic>in vivo<\/jats:italic> but reduced the EBV DNA load in the bone marrow and promoted gp350 antigen escape. CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>LAG-3<jats:sup>+<\/jats:sup> gp350<jats:sup>KI<\/jats:sup>CAR-T cells were predominant in the bone marrow.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The two types of <jats:sup>KO<\/jats:sup>TCR<jats:sup>KI<\/jats:sup>CAR-T cells showed different therapeutic effects and <jats:italic>in vivo<\/jats:italic> dynamics. These findings reflect the complexities of the immune escape mechanisms of EBV, which may interfere with the CAR-T cell property and potency and should be taken into account for future clinical translation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1086433","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T05:06:02Z","timestamp":1679634362000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Non-viral TRAC-knocked-in CD19KICAR-T and gp350KICAR-T cells tested against Burkitt lymphomas with type 1 or 2 EBV infection: In vivo cellular dynamics and 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