{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:56:53Z","timestamp":1791233813386,"version":"4.1.0"},"reference-count":46,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"unspecified","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008258","name":"Hyundai Hope On Wheels","doi-asserted-by":"publisher","award":["NA\/"],"award-info":[{"award-number":["NA\/"]}],"id":[{"id":"10.13039\/100008258","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016193","name":"University of Colorado School of Medicine, Anschutz Medical Campus","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100016193","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,4,7]]},"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>T cells modified to express a chimeric antigen receptor (CAR) are successful against B-lineage malignancies but fail to induce durable remissions in up to half of patients and have shown limited efficacy against other types of cancer. Strategies to improve CAR T cell potency and responses to low antigen densities without inducing CAR T cell dysfunction or limiting persistence are necessary to expand durability of remissions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We overexpressed T-bet in human and mouse CAR T cells to mimic exposure to signal 3 cytokines during T cell priming to promote T helper cell 1 (Th1) polarization of CD4+CAR\u2009T cells with the goal of enhancing antitumor activity. Using human CAR T cells and xenograft models we interrogated the impact of T-bet overexpression on CAR T cell antitumor activity in vitro and in vivo. We also used a syngeneic murine CAR T cell model to study the impact of T-bet overexpression on long-term persistence and secondary responses to tumor rechallenge.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>T-bet overexpression reduced expression of the Th2 cytokine interleukin 4 and promoted polyfunctional production of Th1-associated cytokines in response to CAR stimulation. T-bet overexpression enhanced some effector functions in vitro but did not improve CAR T cell-mediated control of leukemia expressing high levels of antigen in vivo. T-bet overexpression also improved effector function of murine CD19 CAR T cells with no impairment to the persistence or ability of persistent CAR T cells to re-expand and clear a secondary leukemia challenge. Finally, T-bet overexpression promoted enhanced in vitro function against leukemia expressing low levels of CD19, which translated to improved control of CD19lo leukemia in vivo by human C19 CAR T cells containing a 4-1BB costimulatory domain.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Together, our data demonstrate that T-bet overexpression induces a reduction in Th2 cytokine production, an increase in polyfunctional Th1 cytokine production and enhances 4-1BB CAR T cell activity against cancers expressing low levels of target antigen without promoting a loss in functional CAR T cell persistence.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010962","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T20:15:27Z","timestamp":1744920927000},"page":"e010962","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["T-bet overexpression enhances CAR T cell effector functions and antigen sensitivity"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8111-8697","authenticated-orcid":false,"given":"Jennifer M","family":"Cimons","sequence":"first","affiliation":[{"name":"Pediatrics Hematolgy\/Oncology\/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kole R","family":"DeGolier","sequence":"additional","affiliation":[{"name":"Pediatrics Hematolgy\/Oncology\/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel D","family":"Burciaga","sequence":"additional","affiliation":[{"name":"Pediatrics Hematolgy\/Oncology\/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C","family":"Yarnell","sequence":"additional","affiliation":[{"name":"Pediatrics Hematolgy\/Oncology\/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8780-7395","authenticated-orcid":false,"given":"Amanda J","family":"Novak","sequence":"additional","affiliation":[{"name":"Pediatrics Hematolgy\/Oncology\/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia M","family":"Rivera-Reyes","sequence":"additional","affiliation":[{"name":"Pediatrics Hematolgy\/Oncology\/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1181-0418","authenticated-orcid":false,"given":"M. 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