{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T03:15:54Z","timestamp":1794107754518,"version":"4.8.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2020,10]]},"DOI":"10.1038\/s41591-020-1081-3","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T12:05:43Z","timestamp":1601899543000},"page":"1569-1575","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":440,"title":["Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4336-1071","authenticated-orcid":false,"given":"Nirav N.","family":"Shah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryon D.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenlu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8129-0614","authenticated-orcid":false,"given":"Aniko","family":"Szabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3085-6876","authenticated-orcid":false,"given":"Carolyn A.","family":"Keever-Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Worden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Kadan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6442-1320","authenticated-orcid":false,"given":"Sharon","family":"Yim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5372-510X","authenticated-orcid":false,"given":"Mehdi","family":"Hamadani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy S.","family":"Fenske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3861-7677","authenticated-orcid":false,"given":"Boro","family":"Dropuli\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rimas","family":"Orentas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parameswaran","family":"Hari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,5]]},"reference":[{"key":"1081_CR1","doi-asserted-by":"publisher","first-page":"2531","DOI":"10.1056\/NEJMoa1707447","volume":"377","author":"SS Neelapu","year":"2017","unstructured":"Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531\u20132544 (2017).","journal-title":"N. Engl. J. Med."},{"key":"1081_CR2","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1056\/NEJMoa1804980","volume":"380","author":"SJ Schuster","year":"2018","unstructured":"Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45\u201356 (2018).","journal-title":"N. Engl. J. Med"},{"key":"1081_CR3","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.1056\/NEJMoa1708566","volume":"377","author":"SJ Schuster","year":"2017","unstructured":"Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545\u20132554 (2017).","journal-title":"N. Engl. J. Med."},{"key":"1081_CR4","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1056\/NEJMoa1709866","volume":"378","author":"SL Maude","year":"2018","unstructured":"Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439\u2013448 (2018).","journal-title":"N. Engl. J. Med."},{"key":"1081_CR5","doi-asserted-by":"publisher","first-page":"2593","DOI":"10.1056\/NEJMe1714680","volume":"377","author":"E Tran","year":"2017","unstructured":"Tran, E., Longo, D. L. & Urba, W. J. A milestone for CAR T cells. N. Engl. J. Med. 377, 2593\u20132596 (2017).","journal-title":"N. Engl. J. Med."},{"key":"1081_CR6","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S1470-2045(18)30864-7","volume":"20","author":"FL Locke","year":"2019","unstructured":"Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1\u20132 trial. Lancet Oncol. 20, 31\u201342 (2019).","journal-title":"Lancet Oncol."},{"key":"1081_CR7","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1182\/blood-2019-127508","volume":"134","author":"JS Abramson","year":"2019","unstructured":"Abramson, J. S. et al. Pivotal safety and efficacy results from transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed\/refractory (R\/R) large B cell lymphomas. Blood 134, 241 (2019).","journal-title":"Blood"},{"key":"1081_CR8","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1158\/2159-8290.CD-15-1020","volume":"5","author":"E Sotillo","year":"2015","unstructured":"Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282\u20131295 (2015).","journal-title":"Cancer Discov."},{"key":"1081_CR9","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.1038\/s41591-018-0146-z","volume":"24","author":"EJ Orlando","year":"2018","unstructured":"Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504\u20131506 (2018).","journal-title":"Nat. Med."},{"key":"1081_CR10","first-page":"372","volume":"16","author":"NN Shah","year":"2019","unstructured":"Shah, N. N. & Fry, T. J. Mechanisms of resistance to CAR T cell therapy. Nat. Rev. Clin. Oncol. 16, 372\u2013385 (2019).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"1081_CR11","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/s41586-019-1054-1","volume":"568","author":"M Hamieh","year":"2019","unstructured":"Hamieh, M. et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature 568, 112\u2013116 (2019).","journal-title":"Nature"},{"key":"1081_CR12","doi-asserted-by":"publisher","first-page":"7517","DOI":"10.1200\/JCO.2019.37.15_suppl.7517","volume":"37","author":"JY Spiegel","year":"2019","unstructured":"Spiegel, J. Y. et al. Outcomes in large B-cell lymphoma progressing after axicabtagene ciloleucel (axi-cel): results from the US Lymphoma CAR-T Consortium. J. Clin. Oncol. 37, 7517 (2019).","journal-title":"J. Clin. Oncol."},{"key":"1081_CR13","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1182\/blood-2019-126218","volume":"134","author":"SS Neelapu","year":"2019","unstructured":"Neelapu, S. S. et al. CD19 loss with preservation of other B cell lineage features in patients with large B cell lymphoma who relapsed post-axi-cel. Blood 134, 203 (2019).","journal-title":"Blood"},{"key":"1081_CR14","doi-asserted-by":"crossref","unstructured":"Shah, N. N., Maatman, T., Hari, P. & Johnson, B. Multi-targeted CAR T-cell therapies for B-cell malignancies. Front. Oncol. 9, 146 (2019).","DOI":"10.3389\/fonc.2019.00146"},{"key":"1081_CR15","doi-asserted-by":"crossref","unstructured":"Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219\u20131226 (2018).","DOI":"10.1158\/2159-8290.CD-18-0442"},{"key":"1081_CR16","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1158\/2326-6066.CIR-15-0231","volume":"4","author":"E Zah","year":"2016","unstructured":"Zah, E. et al. T cells expressing CD19\/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 498\u2013508 (2016).","journal-title":"Cancer Immunol. Res."},{"key":"1081_CR17","doi-asserted-by":"crossref","unstructured":"Schneider, D. et al. A tandem CD19\/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J. Immunother. Cancer 5, 42 (2017).","DOI":"10.1186\/s40425-017-0246-1"},{"key":"1081_CR18","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","volume":"25","author":"DW Lee","year":"2018","unstructured":"Lee, D. W. et al. ASBMT consensus grading for cytokine release syndrome and neurological toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625\u2013638 (2018).","journal-title":"Biol. Blood Marrow Transplant."},{"key":"1081_CR19","doi-asserted-by":"crossref","unstructured":"Teachey, D. T. et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 6, 664\u2013679 (2016).","DOI":"10.1158\/2159-8290.CD-16-0040"},{"key":"1081_CR20","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0343-9","volume":"6","author":"A Shimabukuro-Vornhagen","year":"2018","unstructured":"Shimabukuro-Vornhagen, A. et al. Cytokine release syndrome. J. Immunother. Cancer 6, 56 (2018).","journal-title":"J. Immunother. Cancer"},{"key":"1081_CR21","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/s41409-019-0602-5","volume":"54","author":"CK Chou","year":"2019","unstructured":"Chou, C. K. & Turtle, C. J. Insight into mechanisms associated with cytokine release syndrome and neurotoxicity after CD19 CAR T-cell immunotherapy. Bone Marrow Transplant. 54, 780\u2013784 (2019).","journal-title":"Bone Marrow Transplant."},{"key":"1081_CR22","doi-asserted-by":"crossref","unstructured":"Hay, K. A. et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T cell therapy. Blood 130, 2295\u20132306 (2017).","DOI":"10.1182\/blood-2017-06-793141"},{"key":"1081_CR23","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.jcyt.2017.09.005","volume":"20","author":"F Zhu","year":"2018","unstructured":"Zhu, F. et al. Closed-system manufacturing of CD19 and dual-targeted CD20\/19 chimeric antigen receptor T cells using the CliniMACS Prodigy device at an academic medical center. Cytotherapy 20, 394\u2013406 (2018).","journal-title":"Cytotherapy"},{"key":"1081_CR24","doi-asserted-by":"publisher","unstructured":"Tong C. et al. Optimized tandem CD19\/CD20 CAR-engineered T cells in refractory\/relapsed B cell lymphoma. Blood https:\/\/doi.org\/10.1182\/blood.2020005278 (2020).","DOI":"10.1182\/blood.2020005278"},{"key":"1081_CR25","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1182\/blood-2018-99-110142","volume":"132","author":"N Hossain","year":"2018","unstructured":"Hossain, N. et al. Phase I experience with a bi-specific CAR targeting CD19 and CD22 in adults with B-cell malignancies. Blood 132, 490 (2018).","journal-title":"Blood"},{"key":"1081_CR26","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1182\/blood.2019003293","volume":"135","author":"J Pan","year":"2020","unstructured":"Pan, J. et al. Sequential CD19-22 CAR T therapy induces sustained remission in children with r\/r B-ALL. Blood 135, 387\u2013391 (2020).","journal-title":"Blood"},{"key":"1081_CR27","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.cryobiol.2008.06.002","volume":"57","author":"PV Jeurink","year":"2008","unstructured":"Jeurink, P. V. et al. T cell responses in fresh and cryopreserved peripheral blood mononuclear cells: kinetics of cell viability, cellular subsets, proliferation, and cytokine production. Cryobiology 57, 91\u2013103 (2008).","journal-title":"Cryobiology"},{"key":"1081_CR28","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1016\/j.ymthe.2019.05.015","volume":"27","author":"SR Panch","year":"2019","unstructured":"Panch, S. R. et al. Effect of cryopreservation on autologous chimeric antigen receptor T cell characteristics. Mol. Ther. 27, 1275\u20131285 (2019).","journal-title":"Mol. Ther."},{"key":"1081_CR29","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1200\/JCO.2013.54.8800","volume":"32","author":"BD Cheson","year":"2014","unstructured":"Cheson, B. D. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J. Clin. Oncol. 32, 3059\u20133068 (2014).","journal-title":"J. Clin. Oncol."},{"key":"1081_CR30","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"},{"key":"1081_CR31","unstructured":"US Department of Health and Human Services. Common Terminology Criteria for Adverse Events version 5.0 (US Department of Health and Human Services, 2017)."},{"key":"1081_CR32","doi-asserted-by":"publisher","first-page":"5446","DOI":"10.1182\/blood-2007-06-093906","volume":"111","author":"M Hallek","year":"2008","unstructured":"Hallek, M. et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute\u2013Working Group 1996 guidelines. Blood 111, 5446\u20135456 (2008).","journal-title":"Blood"}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-020-1081-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-020-1081-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-020-1081-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T20:49:19Z","timestamp":1633380559000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-020-1081-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10]]},"references-count":32,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["1081"],"URL":"https:\/\/doi.org\/10.1038\/s41591-020-1081-3","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10]]},"assertion":[{"value":"16 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"N.N.S. reports honoraria, travel support and research funding from Miltenyi Biotec; honoraria from Incyte and Celgene; service on scientific advisory boards for Kite, Celgene, TG Therapeutics and Lily; and institutional research support for clinical trials from BMS and Miltenyi Biotec. D.S. reports employment with Lentigen, a Miltenyi Biotec company. B.D.J. reports travel support and research funding from Miltenyi Biotec. A.S. has no competing financial interest with regard to this submission. F.Z. has no competing financial interests with regard to this submission. C.A.K.-T. has no competing financial interest with regard to this submission. W.K. reports employment with Lentigen, a Miltenyi Biotec company. A.A.W. reports employment with Lentigen, a Miltenyi Biotec company. M.J.K. reports employment with Lentigen, a Miltenyi Biotec company. S.Y. has no competing financial interest with regard to this submission. A.C. has no competing financial interest with regard to this submission. M.H. reports research support funding from Takeda Pharmaceutical Company and Spectrum Pharmaceuticals; consultancy with Incyte Corporation, ADC Therapeutics, Celgene, Pharmacyclics, Omeros and Verastem; and speaker\u2019s bureau with Sanofi Genzyme and AstraZeneca. T.S.F. reports research funding from Millennium, Kyowa, TG Therapeutics, Portola and Curis; consulting honoraria from Genentech, Adaptive Biotechnologies, AbbVie, Verastem, Kite and MorphoSys; and speaking honoraria from Genentech, Sanofi, Seattle Genetics, AstraZeneca, Celgene and Adaptive Biotechnologies. B.D. reports employment with Lentigen, a Miltenyi Biotec company. R.O. reports prior employment and an ongoing consulting relationship with and research support from Lentigen, a Miltenyi Biotec company, and consulting for Umoja Biopharma. P.H. reports honoraria and travel support from Miltenyi Biotec; research grants from BMS, Takeda, Janssen and Bluebird; and honoraria from BMS, Takeda, Amgen, Karyopharm, Janssen, Incyte, Sanofi and GSK.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}