{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:24:46Z","timestamp":1793744686412,"version":"4.6.1"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T00:00:00Z","timestamp":1713571200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T00:00:00Z","timestamp":1713571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R\/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA\/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I\/II study of BC19 CAR T cells in 50 patients with R\/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R\/R MM.<\/jats:p>","DOI":"10.1038\/s41467-024-47801-8","type":"journal-article","created":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T06:01:56Z","timestamp":1713592916000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed\/refractory multiple myeloma: a phase I\/II trial"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9263-6468","authenticated-orcid":false,"given":"Ming","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaojiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-4674","authenticated-orcid":false,"given":"Hongming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8157-4908","authenticated-orcid":false,"given":"Dan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-6577","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7856-2651","authenticated-orcid":false,"given":"Zhiling","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1170-7074","authenticated-orcid":false,"given":"Wei","family":"Sang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0717-9133","authenticated-orcid":false,"given":"Kunming","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Depeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9356-2154","authenticated-orcid":false,"given":"Feng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4610-9135","authenticated-orcid":false,"given":"Zhenyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7988-2935","authenticated-orcid":false,"given":"Jianlin","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1886-2978","authenticated-orcid":false,"given":"Qingyun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6930-8965","authenticated-orcid":false,"given":"Lingyu","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-7755","authenticated-orcid":false,"given":"Xiaoming","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4913-1610","authenticated-orcid":false,"given":"Weiying","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1375-1084","authenticated-orcid":false,"given":"Kailin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-6410","authenticated-orcid":false,"given":"Junnian","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3767-9283","authenticated-orcid":false,"given":"Jiang","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,20]]},"reference":[{"key":"47801_CR1","doi-asserted-by":"publisher","first-page":"4320","DOI":"10.3390\/cancers13174320","volume":"13","author":"L Gengenbach","year":"2021","unstructured":"Gengenbach, L. et al. Choosing the right therapy for patients with relapsed\/refractory multiple myeloma (RRMM) in consideration of patient-, disease- and treatment-related factors. Cancers\\ 13, 4320 (2021).","journal-title":"Cancers\\"},{"key":"47801_CR2","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1038\/s41375-019-0435-7","volume":"33","author":"UH Gandhi","year":"2019","unstructured":"Gandhi, U. H. et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia 33, 2266\u20132275 (2019).","journal-title":"Leukemia"},{"key":"47801_CR3","doi-asserted-by":"crossref","unstructured":"Martin, T. et al. Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-Cell therapy, for relapsed\/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J. Clin. Oncol. 41, 1265\u20131274 (2023).","DOI":"10.1200\/JCO.22.00842"},{"key":"47801_CR4","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s13045-018-0681-6","volume":"11","author":"WH Zhao","year":"2018","unstructured":"Zhao, W. H. et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J. Hematol. Oncol. 11, 141 (2018).","journal-title":"J. Hematol. Oncol."},{"key":"47801_CR5","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.1172\/JCI126397","volume":"129","author":"AD Cohen","year":"2019","unstructured":"Cohen, A. D. et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Invest. 129, 2210\u20132221 (2019).","journal-title":"J. Clin. Invest."},{"key":"47801_CR6","doi-asserted-by":"publisher","first-page":"2890","DOI":"10.1182\/blood.2020008936","volume":"137","author":"D Wang","year":"2021","unstructured":"Wang, D. et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed\/refractory multiple myeloma. Blood 137, 2890\u20132901 (2021).","journal-title":"Blood"},{"key":"47801_CR7","doi-asserted-by":"publisher","first-page":"2267","DOI":"10.1200\/JCO.2018.77.8084","volume":"36","author":"JN Brudno","year":"2018","unstructured":"Brudno, J. N. et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36, 2267\u20132280 (2018).","journal-title":"J. Clin. Oncol."},{"key":"47801_CR8","doi-asserted-by":"publisher","first-page":"9543","DOI":"10.1073\/pnas.1819745116","volume":"116","author":"J Xu","year":"2019","unstructured":"Xu, J. et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed\/refractory multiple myeloma. Proc. Natl Acad. Sci. USA 116, 9543\u20139551 (2019).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"47801_CR9","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1056\/NEJMoa2024850","volume":"384","author":"NC Munshi","year":"2021","unstructured":"Munshi, N. C. et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 384, 705\u2013716 (2021).","journal-title":"N. Engl. J. Med."},{"key":"47801_CR10","doi-asserted-by":"publisher","first-page":"3002","DOI":"10.1038\/s41375-021-01269-3","volume":"35","author":"L Han","year":"2021","unstructured":"Han, L. et al. Single VHH-directed BCMA CAR-T cells cause remission of relapsed\/refractory multiple myeloma. Leukemia 35, 3002\u20133006 (2021).","journal-title":"Leukemia"},{"key":"47801_CR11","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1186\/s13045-021-01170-7","volume":"14","author":"H Mei","year":"2021","unstructured":"Mei, H. et al. A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma. J. Hematol. Oncol. 14, 161 (2021).","journal-title":"J. Hematol. Oncol."},{"key":"47801_CR12","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s13045-020-00856-8","volume":"13","author":"H Dai","year":"2020","unstructured":"Dai, H. et al. Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. J. Hematol. Oncol. 13, 30 (2020).","journal-title":"J. Hematol. 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Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat. Med. 26, 1569\u20131575 (2020).","journal-title":"Nat. Med."},{"key":"47801_CR16","doi-asserted-by":"publisher","first-page":"2332","DOI":"10.1182\/blood-2003-09-3064","volume":"103","author":"W Matsui","year":"2004","unstructured":"Matsui, W. et al. Characterization of clonogenic multiple myeloma cells. Blood 103, 2332\u20132336 (2004).","journal-title":"Blood"},{"key":"47801_CR17","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1038\/leu.2016.211","volume":"31","author":"B Paiva","year":"2017","unstructured":"Paiva, B. et al. Differentiation stage of myeloma plasma cells: biological and clinical significance. Leukemia 31, 382\u2013392 (2017).","journal-title":"Leukemia"},{"key":"47801_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10948-w","volume":"10","author":"T Nerreter","year":"2019","unstructured":"Nerreter, T. et al. Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T. Nat. Commun. 10, 3137 (2019).","journal-title":"Nat. Commun."},{"key":"47801_CR19","doi-asserted-by":"publisher","first-page":"e127684","DOI":"10.1172\/jci.insight.127684","volume":"4","author":"AL Garfall","year":"2019","unstructured":"Garfall, A. L. et al. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI Insight 4, e127684 (2019).","journal-title":"JCI Insight"},{"key":"47801_CR20","doi-asserted-by":"publisher","first-page":"2246","DOI":"10.1200\/JCO.21.01676","volume":"40","author":"Y Wang","year":"2022","unstructured":"Wang, Y. et al. Long-term follow-up of combination of B-cell maturation Antigen and CD19 chimeric antigen receptor T cells in multiple myeloma. J. Clin. Oncol. 40, 2246\u20132256 (2022).","journal-title":"J. Clin. 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J. et al. \u03b3-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood 134, 1585\u20131597 (2019).","journal-title":"Blood"},{"key":"47801_CR24","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nrclinonc.2017.148","volume":"15","author":"SS Neelapu","year":"2018","unstructured":"Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47\u201362 (2018).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"47801_CR25","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.3390\/ijms20051248","volume":"20","author":"L Rasche","year":"2019","unstructured":"Rasche, L., Kort\u00fcm, K. M., Raab, M. S. & Weinhold, N. The impact of tumor heterogeneity on diagnostics and novel therapeutic strategies in multiple myeloma. Int J. Mol. Sci. 20, 1248 (2019).","journal-title":"Int J. Mol. 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Haematologica 106, 2667\u20132672 (2021).","journal-title":"Haematologica"},{"key":"47801_CR29","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/S0140-6736(21)00933-8","volume":"398","author":"JG Berdeja","year":"2021","unstructured":"Berdeja, J. G. et al. 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. Lancet 398, 314\u2013324 (2021).","journal-title":"Lancet"},{"key":"47801_CR30","doi-asserted-by":"publisher","first-page":"1908","DOI":"10.1038\/leu.2012.120","volume":"26","author":"JJ van Dongen","year":"2012","unstructured":"van Dongen, J. J. et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia 26, 1908\u20131975 (2012).","journal-title":"Leukemia"},{"key":"47801_CR31","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1182\/blood-2014-05-552729","volume":"124","author":"DW Lee","year":"2014","unstructured":"Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188\u2013195 (2014).","journal-title":"Blood"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47801-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47801-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47801-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T06:02:05Z","timestamp":1713592925000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-47801-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,20]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["47801"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-47801-8","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,20]]},"assertion":[{"value":"24 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3371"}}