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CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T\u2010cell activating and costimulatory domains. CARs allow redirection of T\u2010cell cytotoxicity against any antigen of choice, independent of MHC expression. Patient T cells engineered to express CARs specific for CD19 have yielded remarkable outcomes in subjects with relapsed\/refractory B\u2010 cell malignancies, setting off unprecedented interest in T\u2010cell engineering and cell\u2010based cancer immunotherapy. In this review, we present the challenges to extend the use of CAR T cells to solid tumors and other pathologies. We further highlight progress in CAR design, cell manufacturing, and genome editing, which in aggregate hold the promise of generating safer and more effective genetically instructed immunity. Novel engineered cell types, including innate T\u2010cell types, natural killer (NK) cells, macrophages, and induced pluripotent stem cell\u2010derived immune cells, are on the horizon, as are applications of CAR T cells to treat autoimmunity, severe infections, and senescence\u2010associated pathologies.<\/jats:p>","DOI":"10.1002\/eji.202049064","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T04:51:36Z","timestamp":1625201496000},"page":"2151-2163","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["CAR T cells: Building on the CD19 paradigm"],"prefix":"10.1002","volume":"51","author":[{"given":"Anat","family":"Globerson Levin","sequence":"first","affiliation":[{"name":"Immunology Lab Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Rivi\u00e8re","sequence":"additional","affiliation":[{"name":"Center for Cell Engineering Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelig","family":"Eshhar","sequence":"additional","affiliation":[{"name":"Immunology Lab Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Sadelain","sequence":"additional","affiliation":[{"name":"Center for Cell Engineering Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80010"},{"key":"e_1_2_12_3_1","first-page":"802","article-title":"CD19\u2010Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B\u2010cell acute lymphoblastic leukemia","volume":"14","author":"Davila M. 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