{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:49:23Z","timestamp":1790660963807,"version":"4.1.0"},"reference-count":43,"publisher":"BMJ","issue":"12","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2016,11,30]]},"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r\/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r\/r B-ALL.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and analysis<\/jats:title>\n                  <jats:p>This study is a phase I clinical trial for patients with r\/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2\u2005years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-\u03b3, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-\u03b1, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-\u03b1, MIP1-\u03b2 and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system. In addition, patients with grade 3 or 4 neurotoxicities or persistent B-cell aplasia will be treated with dexamethasone (10\u2005mg intravenously every 6\u2005hours) or IgG, respectively. Descriptive and analytical analyses will be performed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Ethics and dissemination<\/jats:title>\n                  <jats:p>Ethical approval for the study was granted on 10 July 2014 (YLJS-2014-7-10). Written informed consent will be taken from all participants. The results of the study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02186860\" ext-link-type=\"uri\">NCT02186860<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjopen-2016-013904","type":"journal-article","created":{"date-parts":[[2016,12,30]],"date-time":"2016-12-30T20:40:16Z","timestamp":1483130416000},"page":"e013904","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":72,"title":["Third-generation CD28\/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol"],"prefix":"10.1136","volume":"6","clinical-trial-number":[{"clinical-trial-number":"nct02186860","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Xiao-Yi","family":"Tang","sequence":"first","affiliation":[{"name":"Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[{"name":"Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Liang","family":"Hu","sequence":"additional","affiliation":[{"name":"Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cao","sequence":"additional","affiliation":[{"name":"Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan-Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China"},{"name":"Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Chen","sequence":"additional","affiliation":[{"name":"Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China"},{"name":"Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2016,12,30]]},"reference":[{"key":"2025101810375674000_6.12.e013904.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60457-2"},{"key":"2025101810375674000_6.12.e013904.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1001294"},{"key":"2025101810375674000_6.12.e013904.3","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3258"},{"key":"2025101810375674000_6.12.e013904.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466"},{"key":"2025101810375674000_6.12.e013904.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1412082"},{"key":"2025101810375674000_6.12.e013904.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1501824"},{"key":"2025101810375674000_6.12.e013904.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00561-4"},{"key":"2025101810375674000_6.12.e013904.8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32446"},{"key":"2025101810375674000_6.12.e013904.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0040865"},{"key":"2025101810375674000_6.12.e013904.10","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403302"},{"key":"2025101810375674000_6.12.e013904.11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0160"},{"key":"2025101810375674000_6.12.e013904.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.24.10024"},{"key":"2025101810375674000_6.12.e013904.13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.1.104"},{"key":"2025101810375674000_6.12.e013904.14","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.83"},{"key":"2025101810375674000_6.12.e013904.15","doi-asserted-by":"crossref","unstructured":"Gardner RA , Finney O , Smithers H , et al . Prolonged functional persistence of CD19CAR t cell products of defined CD4:CD8 composition and transgene expression determines durability of MRD-negative ALL remission. J Clin Oncol 2016;34 (Suppl) ; abstr 3048.","DOI":"10.1200\/JCO.2016.34.15_suppl.3048"},{"key":"2025101810375674000_6.12.e013904.16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-04-348540"},{"key":"2025101810375674000_6.12.e013904.17","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005930"},{"key":"2025101810375674000_6.12.e013904.18","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3008226"},{"key":"2025101810375674000_6.12.e013904.19","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1182\/blood.V126.23.682.682","article-title":"Implications of minimal residual disease negative complete remission (MRD-CR) and allogeneic stem cell transplant on safety and clinical outcome of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed, refractory B-cell ALL","volume":"126","author":"Park","year":"2015","journal-title":"Blood"},{"key":"2025101810375674000_6.12.e013904.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61403-3"},{"key":"2025101810375674000_6.12.e013904.21","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1182\/blood.V126.23.684.684","article-title":"Safety and response of incorporating CD19 chimeric antigen receptor T cell therapy in typical salvage regimens for children and young adults with acute lymphoblastic leukemia","volume":"126","author":"Lee","year":"2015","journal-title":"Blood"},{"key":"2025101810375674000_6.12.e013904.22","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.5929"},{"key":"2025101810375674000_6.12.e013904.23","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1182\/blood.V126.23.99.99","article-title":"Allogeneic T-cells expressing an anti-CD19 chimeric antigen receptor cause remissions of B-cell malignancies after allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease","volume":"126","author":"Brudno","year":"2015","journal-title":"Blood"},{"key":"2025101810375674000_6.12.e013904.24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407222"},{"key":"2025101810375674000_6.12.e013904.25","doi-asserted-by":"crossref","unstructured":"Maude SL , Teachey DT , Rheingold SR , et al . Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed\/refractory ALL. J Clin Oncol 2016;34(Suppl ); abstr 3011.","DOI":"10.1200\/JCO.2016.34.15_suppl.3011"},{"key":"2025101810375674000_6.12.e013904.26","doi-asserted-by":"crossref","unstructured":"Maude SL , Barrett DM , Rheingold SR , et al . Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children with relapsed ALL. J Clin Oncol 2016;34 (Suppl); abstr 3007.","DOI":"10.1200\/JCO.2016.34.15_suppl.3007"},{"key":"2025101810375674000_6.12.e013904.27","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-06-506741"},{"key":"2025101810375674000_6.12.e013904.28","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2015.1027469"},{"key":"2025101810375674000_6.12.e013904.29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI85309"},{"key":"2025101810375674000_6.12.e013904.30","doi-asserted-by":"crossref","unstructured":"Turtle CJ , Hanafi LA , Berger C , et al . Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells. J Clin Oncol 2016;34 (Suppl) ; abstr 102.","DOI":"10.1200\/JCO.2016.34.15_suppl.102"},{"key":"2025101810375674000_6.12.e013904.31","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1172\/JCI86721","article-title":"Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells","volume":"126","author":"Kebriaei","year":"2016","journal-title":"J Clin Invest"},{"key":"2025101810375674000_6.12.e013904.32","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s13045-016-0299-5","article-title":"Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy","volume":"9","author":"Hu","year":"2016","journal-title":"J Hematol Oncol"},{"key":"2025101810375674000_6.12.e013904.33","doi-asserted-by":"crossref","first-page":"3774","DOI":"10.1182\/blood.V126.23.3774.3774","article-title":"Chimeric antigen receptor 4SCAR19-modified T cells in acute lymphoid leukemia: a phase II multi-center clinical trial in China","volume":"126","author":"Dong","year":"2015","journal-title":"Blood"},{"key":"2025101810375674000_6.12.e013904.34","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4597"},{"key":"2025101810375674000_6.12.e013904.35","doi-asserted-by":"crossref","first-page":"e0144787","DOI":"10.1371\/journal.pone.0144787","article-title":"Evaluation of intracellular signaling downstream chimeric antigen receptors","volume":"10","author":"Karlsson","year":"2015","journal-title":"PLoS ONE"},{"key":"2025101810375674000_6.12.e013904.36","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-552729"},{"key":"2025101810375674000_6.12.e013904.37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-703751"},{"key":"2025101810375674000_6.12.e013904.38","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-09-551937"},{"key":"2025101810375674000_6.12.e013904.39","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-438002"},{"key":"2025101810375674000_6.12.e013904.40","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2013.46"},{"key":"2025101810375674000_6.12.e013904.41","doi-asserted-by":"publisher","DOI":"10.2217\/imt.14.123"},{"key":"2025101810375674000_6.12.e013904.42","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0040"},{"key":"2025101810375674000_6.12.e013904.43","doi-asserted-by":"crossref","first-page":"15040","DOI":"10.1038\/celldisc.2015.40","article-title":"Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA","volume":"1","author":"Bai","year":"2015","journal-title":"Cell Discov"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2016-013904","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T17:38:04Z","timestamp":1760809084000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2016-013904"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,12,30]]},"published-print":{"date-parts":[[2016,12]]}},"alternative-id":["10.1136\/bmjopen-2016-013904"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2016-013904","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12]]}}}