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To address these limitations, we developed a simple single\u2010step CD7\u2010depletion process followed by transduction with a lentiviral vector encoding a CCR4\/CD7 bispecific CAR. CD7\u2010negative (CD7N) CCR4\/CD7 CAR\u2010T cells could expand without experiencing fratricide, unlike the bulk CCR4\/CD7 CAR\u2010T cells. The CD7N CAR\u2010T exhibited robust cytotoxicity against malignant T\u2010cell lines with heterogeneous CD7 and CCR4 expression in vitro and in vivo. Incorporation of EGFRt in the CAR construct allowed elimination by cetuximab in case of adverse events, whereas inclusion of c\u2010Jun in the construct reduced functional exhaustion after repeated tumor challenges in vitro. In comparison to non\u2010transduced CD7N cells and Bulk CAR\u2010T cells, scRNA\u2010seq analysis of CD7N CAR\u2010T cells revealed a unique AQP3+ CD4+ T\u2010cell subset following exposure to tumor cells. This cell subset exhibited broad activation of the Src\/Ras\/ERK and Bcl\u20102 pathways, high levels of\n                    <jats:italic>SOS1<\/jats:italic>\n                    and\n                    <jats:italic>KLF2<\/jats:italic>\n                    expression, and specific ligand\u2010receptor interactions within the tumor necrosis factor superfamily. Collectively, these results suggest that further clinical development of CCR4\/CD7 bispecific CD7N CAR\u2010T cells is warranted, including the AQP3+ subset with\n                    <jats:italic>SOS1<\/jats:italic>\n                    \/\n                    <jats:italic>KLF2<\/jats:italic>\n                    modulation.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521443","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T12:16:08Z","timestamp":1772972168000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Generation of CCR4\/CD7 Bispecific CAR\u2010T Cells Resistant to Fratricide and Exhaustion"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2978-4147","authenticated-orcid":false,"given":"Sile","family":"Li","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong Hong Kong SAR P. 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