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CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7\u2212 T cells to generate CD7-CAR (CD7-CARCD7\u2212) T cells. CD7-CARCD7\u2212 T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in\u00a0vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7\u2212 T cells for the immunotherapy of CD19+ hematological malignancies. Direct comparison of nonselected (bulk) CD19-CAR and CD19-CARCD7\u2212 T cells revealed that CD19-CARCD7\u2212 T\u00a0cells had enhanced antitumor activity compared with their bulk counterparts in\u00a0vitro and in\u00a0vivo. Lastly, to gain insight into the behavior of CD19-CAR T cells with low levels of CD7 gene expression (CD7lo) in humans, we mined single-cell gene and T-cell receptor (TCR) expression data sets from our institutional CD19-CAR T-cell clinical study. CD19-CARCD7lo T cells were present in the initial CD19-CAR T-cell product and could be detected postinfusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed postinfusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than nonresponders (NCT03573700). Thus, CARCD7\u2212 T cells have favorable biological characteristics and may present a promising T-cell subset for adoptive cell therapy of T-ALL and other hematological malignancies.<\/jats:p>","DOI":"10.1182\/blood.2021015020","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T20:06:25Z","timestamp":1659384385000},"page":"2684-2696","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":67,"title":["Engineering naturally occurring CD7\u2212 T cells for the immunotherapy of hematological malignancies"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7653-2247","authenticated-orcid":false,"given":"Abdullah","family":"Freiwan","sequence":"first","affiliation":[{"name":"1Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children\u2019s Research Hospital, Memphis, 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