{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T23:50:37Z","timestamp":1780357837040,"version":"3.54.1"},"reference-count":61,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"unspecified","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"American Society of Gene and Cell Therapy (ASGCT) - Career Development Award 2019","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"SCOR from Leukemia and Lymphoma Society","award":["7001-19"],"award-info":[{"award-number":["7001-19"]}]},{"name":"Alex's Lemonade Stand Foundation for Childhood Cancer Reach Award","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"NIH-NCI","award":["P50 CA126752"],"award-info":[{"award-number":["P50 CA126752"]}]},{"name":"1 SRA VSTs from Tessa Therapeutics, Singapore","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"NIH-NLBI","award":["HHSN268201600015I"],"award-info":[{"award-number":["HHSN268201600015I"]}]},{"name":"Baylor College of Medicine Comprehensive Cancer Training Program CPRIT fellowship","award":["RP160283"],"award-info":[{"award-number":["RP160283"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,3,23]]},"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific T cells from patients. Here, we examine reasons for and solutions to this failure, taking as our model the preparation of Epstein-Barr virus (EBV)-specific T cells (EBVSTs) for the treatment of EBV-positive lymphoma. EBVSTs could not be manufactured from almost one-third of patients, either because they failed to expand, or they expanded, but lacked EBV specificity. We identified an underlying cause of this problem and established a clinically feasible approach to overcome it.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>CD45RO+CD45RA\u2212 memory compartment residing antigen-specific T cells were enriched by depleting CD45RA positive (+) peripheral blood mononuclear cells (PBMCs) that include na\u00efve T cells, among other subsets, prior to EBV antigen stimulation. We then compared the phenotype, specificity, function and T-cell receptor (TCR) V\u03b2 repertoire of EBVSTs expanded from unfractionated whole (W)-PBMCs and CD45RA-depleted (RAD)-PBMCs on day 16. To identify the CD45RA component that inhibited EBVST outgrowth, isolated CD45RA+ subsets were added back to RAD-PBMCs followed by expansion and characterization. The in vivo potency of W-EBVSTs and RAD-EBVSTs was compared in a murine xenograft model of autologous EBV+ lymphoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Depletion of CD45RA+ PBMCs before antigen stimulation increased EBVST expansion, antigen-specificity and potency in vitro and in vivo. TCR sequencing revealed a selective outgrowth in RAD-EBVSTs of clonotypes that expanded poorly in W-EBVSTs. Inhibition of antigen-stimulated T cells by CD45RA+ PBMCs could be reproduced only by the na\u00efve T-cell fraction, while CD45RA+ regulatory T cells, natural killer cells, stem cell memory and effector memory subsets lacked inhibitory activity. Crucially, CD45RA depletion of PBMCs from patients with lymphoma enabled the outgrowth of EBVSTs that failed to expand from W-PBMCs. This enhanced specificity extended to T cells specific for other viruses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our findings suggest that na\u00efve T cells inhibit the outgrowth of antigen-stimulated memory T cells, highlighting the profound effects of intra-T-cell subset interactions. Having overcome our inability to generate EBVSTs from many patients with lymphoma, we have introduced CD45RA depletion into three clinical trials: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01555892\">NCT01555892<\/jats:ext-link> and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04288726\">NCT04288726<\/jats:ext-link> using autologous and allogeneic EBVSTs to treat lymphoma and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04013802\">NCT04013802<\/jats:ext-link> using multivirus-specific T cells to treat viral infections after hematopoietic stem cell transplantation.<\/jats:p>\n               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Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mae","family":"Woods","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital, and Houston Methodist Hospital, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naren U","family":"Mehta","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital, and Houston Methodist Hospital, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Sauer","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital, and Houston Methodist Hospital, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathan S","family":"Parikh","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital, and Houston Methodist Hospital, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schmueck-Henneresse","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital, and Houston Methodist Hospital, Houston, Texas, USA"},{"name":"Berlin Institute of Health (BIH) at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charit\u00e9platz 1, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital, and Houston Methodist Hospital, Houston, Texas, 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