{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:26:05Z","timestamp":1793316365435,"version":"4.5.0"},"reference-count":52,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T00:00:00Z","timestamp":1712534400000},"content-version":"unspecified","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070227 and 82073800"],"award-info":[{"award-number":["82070227 and 82073800"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008750","name":"Shanghai Municipal Hospital Development Center","doi-asserted-by":"publisher","award":["SHDC2020CR2066B"],"award-info":[{"award-number":["SHDC2020CR2066B"]}],"id":[{"id":"10.13039\/501100008750","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,3,18]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1\n                      <jats:sup>KD<\/jats:sup>\n                      BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with parental BCMA CAR-T cells, PD-1\n                      <jats:sup>KD<\/jats:sup>\n                      BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1\n                      <jats:sup>KD<\/jats:sup>\n                      BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4\/7, 57.1%) with at least one extramedullary site and four patients (4\/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6\/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2023-008429","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T13:25:26Z","timestamp":1712582726000},"page":"e008429","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":66,"title":["PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2104-9439","authenticated-orcid":false,"given":"Wanyan","family":"Ouyang","sequence":"first","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Wei","family":"Jin","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai Unicar-Therapy Bio-medicine Technology Co Ltd, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuqingqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"},{"name":"School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqing","family":"Kang","sequence":"additional","affiliation":[{"name":"Shanghai Unicar-Therapy Bio-medicine Technology Co Ltd, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Tao","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[{"name":"Shanghai Unicar-Therapy Bio-medicine Technology Co Ltd, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Qing","family":"Mi","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"2025100315082995000_12.4.e008429.1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S0140-6736(21)00933-8","article-title":"Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b\/2 open-label study","volume":"398","author":"Berdeja","year":"2021","journal-title":"Lancet"},{"key":"2025100315082995000_12.4.e008429.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1817226"},{"key":"2025100315082995000_12.4.e008429.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709866"},{"key":"2025100315082995000_12.4.e008429.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709919"},{"key":"2025100315082995000_12.4.e008429.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819745116"},{"key":"2025100315082995000_12.4.e008429.6","doi-asserted-by":"crossref","DOI":"10.1186\/s13045-022-01301-8","article-title":"Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2)","volume":"15","author":"Zhao","year":"2022","journal-title":"J Hematol Oncol"},{"key":"2025100315082995000_12.4.e008429.7","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1200\/JCO.22.00690","article-title":"Phase II, open-label study of ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor-T-cell therapy, in Chinese patients with relapsed\/refractory multiple myeloma (CARTIFAN-1)","volume":"41","author":"Mi","year":"2023","journal-title":"J Clin Oncol"},{"key":"2025100315082995000_12.4.e008429.8","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-20-0227"},{"key":"2025100315082995000_12.4.e008429.9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41375-019-0669-4","article-title":"Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do better?","volume":"34","author":"D\u2019Agostino","year":"2020","journal-title":"Leukemia"},{"key":"2025100315082995000_12.4.e008429.10","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41571-019-0297-y","article-title":"Engineering strategies to overcome the current roadblocks in CAR T cell therapy","volume":"17","author":"Rafiq","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"2025100315082995000_12.4.e008429.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0184-6"},{"key":"2025100315082995000_12.4.e008429.12","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s43018-021-00241-5","article-title":"Engineering enhanced CAR T-cells for improved cancer therapy","volume":"2","author":"Milone","year":"2021","journal-title":"Nat Cancer"},{"key":"2025100315082995000_12.4.e008429.13","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090331"},{"key":"2025100315082995000_12.4.e008429.14","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.molcel.2019.12.012","article-title":"PD-1 imposes qualitative control of cellular transcriptomes in response to T cell activation","volume":"77","author":"Shimizu","year":"2020","journal-title":"Mol Cell"},{"key":"2025100315082995000_12.4.e008429.15","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.molcel.2020.02.013","article-title":"PD-1: a driver or passenger of T cell exhaustion?","volume":"77","author":"He","year":"2020","journal-title":"Mol Cell"},{"key":"2025100315082995000_12.4.e008429.16","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862"},{"key":"2025100315082995000_12.4.e008429.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.008"},{"key":"2025100315082995000_12.4.e008429.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.013"},{"key":"2025100315082995000_12.4.e008429.19","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0407"},{"key":"2025100315082995000_12.4.e008429.20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-738245"},{"key":"2025100315082995000_12.4.e008429.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-019-0657-3"},{"key":"2025100315082995000_12.4.e008429.22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83092"},{"key":"2025100315082995000_12.4.e008429.23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13045-022-01244-0","article-title":"Chimeric antigen receptors containing the OX40 signalling domain enhance the persistence of T cells even under repeated stimulation with multiple myeloma target cells","volume":"15","author":"Tan","year":"2022","journal-title":"J Hematol Oncol"},{"key":"2025100315082995000_12.4.e008429.24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024850"},{"key":"2025100315082995000_12.4.e008429.25","doi-asserted-by":"crossref","DOI":"10.1038\/s41408-023-00820-y","article-title":"Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma","volume":"13","author":"Bansal","year":"2023","journal-title":"Blood Cancer J"},{"key":"2025100315082995000_12.4.e008429.26","doi-asserted-by":"crossref","DOI":"10.1182\/blood-2020-140243","article-title":"Chimeric antigen receptor T cell therapy in the relapsed or refractory multiple myeloma with extramedullary disease--a single institution observation in China","volume":"136","author":"Wang","year":"2020","journal-title":"Blood"},{"key":"2025100315082995000_12.4.e008429.27","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/hon.2958","article-title":"Efficacy and follow\u2010up of humanized anti\u2010BCMA CAR\u2010T cell therapy in relapsed\/refractory multiple myeloma patients with extramedullary\u2010extraosseous, extramedullary\u2010bone related, and without extramedullary disease","volume":"40","author":"Li","year":"2022","journal-title":"Hematol Oncol"},{"key":"2025100315082995000_12.4.e008429.28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-2031"},{"key":"2025100315082995000_12.4.e008429.29","doi-asserted-by":"crossref","first-page":"720571","DOI":"10.3389\/fimmu.2021.720571","article-title":"Efficacy of humanized anti-BCMA CAR T cell therapy in relapsed\/refractory multiple myeloma patients with and without extramedullary disease","volume":"12","author":"Deng","year":"2021","journal-title":"Front Immunol"},{"key":"2025100315082995000_12.4.e008429.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2017.01.006"},{"key":"2025100315082995000_12.4.e008429.31","doi-asserted-by":"crossref","DOI":"10.1093\/bib\/bbac429","article-title":"ILGBMSH: an interpretable classification model for the shRNA target prediction with ensemble learning algorithm","volume":"23","author":"Zhao","year":"2022","journal-title":"Brief Bioinform"},{"key":"2025100315082995000_12.4.e008429.32","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00191-1"},{"key":"2025100315082995000_12.4.e008429.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.03.012"},{"key":"2025100315082995000_12.4.e008429.34","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021937"},{"key":"2025100315082995000_12.4.e008429.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0600205103"},{"key":"2025100315082995000_12.4.e008429.36","doi-asserted-by":"publisher","DOI":"10.1038\/ni1413"},{"key":"2025100315082995000_12.4.e008429.37","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-2810"},{"key":"2025100315082995000_12.4.e008429.38","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32103"},{"key":"2025100315082995000_12.4.e008429.39","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2446"},{"key":"2025100315082995000_12.4.e008429.40","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.247"},{"key":"2025100315082995000_12.4.e008429.41","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41573-019-0051-2","article-title":"'Off-the-shelf' allogeneic CAR T cells: development and challenges","volume":"19","author":"Depil","year":"2020","journal-title":"Nat Rev Drug Discov"},{"key":"2025100315082995000_12.4.e008429.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0010-1"},{"key":"2025100315082995000_12.4.e008429.43","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41586-022-05140-y","article-title":"Non-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL","volume":"609","author":"Zhang","year":"2022","journal-title":"Nature"},{"key":"2025100315082995000_12.4.e008429.44","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.1.558"},{"key":"2025100315082995000_12.4.e008429.45","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.10.5808"},{"key":"2025100315082995000_12.4.e008429.46","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-793141"},{"key":"2025100315082995000_12.4.e008429.47","first-page":"2430","article-title":"How I treat refractory CRS and ICANS after CAR T-cell therapy","volume":"141","author":"Jain","year":"2023","journal-title":"Blood"},{"key":"2025100315082995000_12.4.e008429.48","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s43018-021-00207-7","article-title":"Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients","volume":"2","author":"Biasco","year":"2021","journal-title":"Nat Cancer"},{"key":"2025100315082995000_12.4.e008429.49","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30206-6"},{"key":"2025100315082995000_12.4.e008429.50","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-16160-5","article-title":"Systematically optimized BCMA\/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma","volume":"11","author":"Zah","year":"2020","journal-title":"Nat Commun"},{"key":"2025100315082995000_12.4.e008429.51","doi-asserted-by":"crossref","first-page":"e521","DOI":"10.1016\/S2352-3026(19)30115-2","article-title":"A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial","volume":"6","author":"Yan","year":"2019","journal-title":"Lancet Haematol"},{"key":"2025100315082995000_12.4.e008429.52","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2422"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2023-008429","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T22:08:40Z","timestamp":1759529320000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2023-008429"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":52,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4,8]]},"published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1136\/jitc-2023-008429"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2023-008429","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4]]}}}