{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T04:59:59Z","timestamp":1789275599071,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T00:00:00Z","timestamp":1620259200000},"content-version":"vor","delay-in-days":125,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19ck0106284h0003"],"award-info":[{"award-number":["19ck0106284h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20ck0106574h0001"],"award-info":[{"award-number":["20ck0106574h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K10103"],"award-info":[{"award-number":["17K10103"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26461574"],"award-info":[{"award-number":["26461574"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin &amp;amp; Trans Imm"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>As the prognosis of relapsed\/refractory (R\/R) acute myeloid leukaemia (AML) remains poor, novel treatment strategies are urgently needed. Clinical trials have shown that chimeric antigen receptor (CAR)\u2010T cells for AML are more challenging than those targeting CD19 in B\u2010cell malignancies. We recently developed <jats:italic>piggyBac<\/jats:italic>\u2010modified ligand\u2010based CAR\u2010T cells that target CD116\/CD131 complexes, also known as the GM\u2010CSF receptor (GMR), for the treatment of juvenile myelomonocytic leukaemia. This study therefore aimed to develop a novel therapeutic method for R\/R AML using GMR CAR\u2010T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To further improve the efficacy of the original GMR CAR\u2010T cells, we have developed novel GMR CAR vectors incorporating a mutated GM\u2010CSF for the antigen\u2010binding domain and G4S spacer. All GMR CAR\u2010T cells were generated using a <jats:italic>piggyBac<\/jats:italic>\u2010based gene transfer system. The anti\u2010tumor effect of GMR CAR\u2010T cells was tested in mouse AML xenograft models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nearly 80% of the AML cells predominant in myelomonocytic leukaemia were found to express CD116. GMR CAR\u2010T cells exhibited potent cytotoxic activities against CD116<jats:sup>+<\/jats:sup> AML cells <jats:italic>in vitro<\/jats:italic>. Furthermore, GMR CAR\u2010T cells incorporating a G4S spacer significantly improved long\u2010term <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> anti\u2010tumor effects. By employing a mutated GM\u2010CSF at residue 21 (E21K), the anti\u2010tumor effects of GMR CAR\u2010T cells were also improved especially in long\u2010term <jats:italic>in vitro<\/jats:italic> settings. Although GMR CAR\u2010T cells exerted cytotoxic effects on normal monocytes, their lethality on normal neutrophils, T cells, B cells and NK cells was minimal.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>GMR CAR\u2010T cell therapy represents a promising strategy for CD116<jats:sup>+<\/jats:sup> R\/R AML.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cti2.1282","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T12:30:34Z","timestamp":1620477034000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Mutated GM\u2010CSF\u2010based CAR\u2010T cells targeting CD116\/CD131 complexes exhibit enhanced anti\u2010tumor effects against acute myeloid leukaemia"],"prefix":"10.1002","volume":"10","author":[{"given":"Aiko","family":"Hasegawa","sequence":"first","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3866-3582","authenticated-orcid":false,"given":"Shoji","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"},{"name":"Center for Advanced Research of Gene and Cell Therapy Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Narimatsu","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Science Shinshu University  Matsumoto Japan"},{"name":"Frontier Technology Research Laboratory Kissei Pharmaceutical Co., Ltd  Azumino Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Nakano","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Science Shinshu University  Matsumoto Japan"},{"name":"Frontier Technology Research Laboratory Kissei Pharmaceutical Co., Ltd  Azumino Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Ohnota","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Science Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Inada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"},{"name":"Department of Drug Discovery Science Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Morokawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikumi","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"},{"name":"Institute for Biomedical Sciences Interdisciplinary Cluster for Cutting Edge Research Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3117-974X","authenticated-orcid":false,"given":"Yuichiro","family":"Ide","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Shinshu University Hospital  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4056-7242","authenticated-orcid":false,"given":"Kazuyuki","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Health and Medical Sciences Graduate School of Medicine Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9038-1710","authenticated-orcid":false,"given":"Haruko","family":"Tashiro","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology Teikyo University School of Medicine  Itabashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4256-9783","authenticated-orcid":false,"given":"Shigeki","family":"Yagyu","sequence":"additional","affiliation":[{"name":"Center for Advanced Research of Gene and Cell Therapy Shinshu University  Matsumoto Japan"},{"name":"Department of Pediatrics Kyoto Prefectural Medical University  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9317-6694","authenticated-orcid":false,"given":"Miyuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"},{"name":"Center for Advanced Research of Gene and Cell Therapy Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0793-815X","authenticated-orcid":false,"given":"Yozo","family":"Nakazawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"},{"name":"Center for Advanced Research of Gene and Cell Therapy Shinshu University  Matsumoto Japan"},{"name":"Institute for Biomedical Sciences Interdisciplinary Cluster for Cutting Edge Research Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-295279"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.43.7384"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-10-551911"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.04.036"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.62.8289"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.153"},{"key":"e_1_2_9_8_1","first-page":"1911","article-title":"Internal tandem duplication of the flt3 gene found in acute myeloid leukemia","volume":"10","author":"Nakao M","year":"1996","journal-title":"Leukemia"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.11.3589"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215134"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407222"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.56.2025"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61403-3"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI85309"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.154"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2014.164"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-12-474056"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0307"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/trf.15199"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-017-0519-7"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8020200"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.208751"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-016-0256-3"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2400794"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-11-844688"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07104.x"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-10-460170"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019004352"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0902-4441.2003.00184.x"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07491.x"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05129.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.13.5838"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0127"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2014.208"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.05.007"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2017.12.003"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2014.05.022"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.214882"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2014.39"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-08-736041"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2010.91"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1253656"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-438002"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-12-164004"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0549-5"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0159"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-14749-3"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-0330"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.12.7647"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-208629"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.127092"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1057-4"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-01-552174"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0010-1"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e3181ad762b"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.140"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2012.244"}],"container-title":["Clinical &amp; Translational Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cti2.1282","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cti2.1282","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cti2.1282","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T19:27:24Z","timestamp":1693596444000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cti2.1282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":56,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1002\/cti2.1282"],"URL":"https:\/\/doi.org\/10.1002\/cti2.1282","archive":["Portico"],"relation":{},"ISSN":["2050-0068","2050-0068"],"issn-type":[{"value":"2050-0068","type":"print"},{"value":"2050-0068","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1]]},"assertion":[{"value":"2020-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1282"}}