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We generated PD-1 and T cell receptor\n                (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9\n                technology and evaluated them in a dose-escalation study. A total of 15 patients\n                received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No\n                dose-limiting toxicity or unexpected adverse events were observed in any of the 15\n                patients. The best overall response was stable disease (2\/15 patients). Circulating\n                MPTK-CAR-T cells peaked at days 7\u201314 and became undetectable beyond 1 month.\n                TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly\n                detected in effusion or peripheral blood from three patients after infusion. We\n                further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal\n                models. Our results establish the preliminary feasibility and safety of\n                CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR\n                plays an important role in the persistence of CAR-T cells when treating solid\n                tumors.<\/jats:p>","DOI":"10.1038\/s41423-021-00749-x","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T03:02:48Z","timestamp":1628650968000},"page":"2188-2198","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":257,"title":["Phase I study of CAR-T cells with PD-1 and TCR disruption in\n              mesothelin-positive solid tumors"],"prefix":"10.1038","volume":"18","author":[{"given":"Zhenguang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaichao","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingming","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianjun","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaping","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-3899","authenticated-orcid":false,"given":"Weidong","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,11]]},"reference":[{"key":"749_CR1","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1158\/2159-8290.CD-15-0583","volume":"6","author":"A Morello","year":"2016","unstructured":"Morello A, Sadelain M, Adusumilli PS. 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In the published version of this article, the group labels in\n                    Fig. 1G were incorrect. In the left panel of Fig. 1G, the group label\n                    \u201cPBS\u201d should have read \u201cPBS (Day46)\u201d, and the\n                    group labels \u201cP4 and MPK\u201d should have read \u201cDay70-P4,\n                    MPK\u201d. In the right panel of Fig. 1G, the group labels \u201cP4 and\n                    MPK\u201d should have read \u201cDay70-P4, MPK\u201d. In addition, the\n                    corresponding sentence in the legend of Fig. 1 read: \u201cTumor growth (F) and\n                    the sizes and weights of resected tumors (G) derived from PDX mice sacrificed at\n                    46 days after CAR-T cell injection.\u201d It has now been corrected to read:\n                    \u201cTumor growth (F) and the sizes and weights of resected tumors (G) derived\n                    from PDX mice sacrificed at 70 days after CAR-T cell injection. The mice in the\n                    control group were sacrificed at 46 days after PBS injection.\u201d The authors\n                    would like to apologize for this error. This correction does not affect the data,\n                    statistical analyses, results, or conclusions of the study. The original article\n                    has been corrected.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"L.J.S., J.P.H., X.Y. and W.C. are employees of Gracell\n                  Biotechnologies (Shanghai) Co., Ltd., whose potential product was studied in this\n                  work. H.Y.W. was a consultant of Gracell Biotechnologies (Shanghai) Co., Ltd.,\n                  Institute of Zoology, Chinese Academy of Sciences, and has a technology assignment\n                  agreement with Gracell Biotechnologies (Shanghai) Co., Ltd., for\n                  CRISPR-Cas9-mediated\n                      PDCD1\n                      and\n                      TRAC\n                      gene editing methods in mesothelin-directed CAR-T\n                  cells.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}