{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:01:43Z","timestamp":1791284503972,"version":"4.1.0"},"reference-count":20,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T00:00:00Z","timestamp":1652054400000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,4,19]]},"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>Chimeric antigen receptor T-cells (CART) are active in relapsed\/refractory (r\/r) B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a substantial challenge. Reinfusion with the same CART product (CART2) in patients with suboptimal response or antigen positive relapse following first infusion (CART1) represents a potential treatment strategy, though early experiences suggest limited efficacy of CART2 with CD19 targeting. We report on our experience with CART2 across a host of novel CAR T-cell trials. This was a retrospective review of children and young adults with B-ALL who received reinfusion with an anti-CD19, anti-CD22, or anti-CD19\/22 CART construct on one of 3 CAR T-cells trials at the National Cancer Institute (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01593696\">NCT01593696<\/jats:ext-link>,  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02315612\">NCT02315612<\/jats:ext-link>, NCT0344839) between July 2012 and January 2021. All patients received lymphodepletion (LD) pre-CART (standard LD: 75\u2009mg\/m<jats:sup>2<\/jats:sup> fludarabine, 900\u2009mg\/m<jats:sup>2<\/jats:sup> cyclophosphamide; or intensified LD: 120\u2009mg\/m<jats:sup>2<\/jats:sup> fludarabine, 1200\u2009mg\/m<jats:sup>2<\/jats:sup> cyclophosphamide). Primary objectives were to describe response to and toxicity of CART2. Indication for CART2, impact of LD intensity, and CAR T-cell expansion and leukemia antigen expression between CART infusions was additionally evaluated. Eighteen patients proceeded to CART2 due to persistent (n=7) or relapsed antigen positive disease (n=11) following CART1. Seven of 18 (38.9%) demonstrated objective response (responders) to CART2: 5 achieved a minimal residual disease (MRD) negative CR, 1 had persistent MRD level disease, and 1 showed a partial remission, the latter with eradication of antigen positive disease and emergence of antigen negative B-ALL. Responders included four patients who had not achieved a CR with CART1. Limited cytokine release syndrome was seen following CART2. Peripheral blood CART1 expansion was higher than CART2 expansion (p=0.03). Emergence of antigen negative\/dim B-ALL in 6 (33.3%) patients following CART2 contributed to lack of CR. Five of seven (71.4%) responders received intensified LD pre-CART2, which corresponded with higher CART2 expansion than in those receiving standard LD (p=0.029). Diminished CAR T-cell expansion and antigen downregulation\/loss impeded robust responses to CART2. A subset of patients, however, may derive benefit from CART2 despite suboptimal response to CART1. Intensified LD may be one strategy to augment CART2 responses, though further study of factors associated with CART2 response, including serial monitoring of antigen expression, is warranted.<\/jats:p>","DOI":"10.1136\/jitc-2021-004483","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T12:48:52Z","timestamp":1653310132000},"page":"e004483","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct01593696","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02315612","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03827343","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01593696","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02315612","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04225676","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Elizabeth M","family":"Holland","sequence":"first","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3142-516X","authenticated-orcid":false,"given":"John C","family":"Molina","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"},{"name":"Department of Pediatric Oncology, Johns Hopkins Hospital, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kniya","family":"Dede","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Moyer","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance M","family":"Yuan","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryalice","family":"Stetler-Stevenson","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Mackall","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"},{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"},{"name":"Division of Hematology\/Oncology\/SCT and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA"},{"name":"Division of Stem Cell Transplant and Cell Therapy, Department of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry J","family":"Fry","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"},{"name":"University of Colorado Anschutz Medical Campus and Center for Cancer and Blood Disorders, Children\u2019s Hospital of Colorado, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandhya","family":"Panch","sequence":"additional","affiliation":[{"name":"Center for Cellular Engineering, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Highfill","sequence":"additional","affiliation":[{"name":"Center for Cellular Engineering, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Stroncek","sequence":"additional","affiliation":[{"name":"Center for Cellular Engineering, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Little","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W","family":"Lee","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"},{"name":"Division of Pediatric Hematology\/Oncology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8692-8034","authenticated-orcid":false,"given":"Haneen","family":"Shalabi","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie","family":"Yates","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8474-9080","authenticated-orcid":false,"given":"Nirali","family":"Shah","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Insitutes of Health, Bethesda, Maryland, 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Tisagenlecleucel immunogenicity in relapsed\/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. 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