{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T23:49:32Z","timestamp":1782258572293,"version":"3.54.5"},"reference-count":54,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development and Innovation Office, Hungary","award":["K119690"],"award-info":[{"award-number":["K119690"]}]},{"name":"National Research, Development and Innovation Office, Hungary","award":["FK132773"],"award-info":[{"award-number":["FK132773"]}]},{"name":"European Union and the European Regional Development Fund","award":["GINOP-2.3.2-15-2016-00044, -00050"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00044, -00050"]}]},{"DOI":"10.13039\/501100003825","name":"Hungarian Academy of Sciences","doi-asserted-by":"publisher","award":["J\u00e1nos Bolyai Research Scholarship"],"award-info":[{"award-number":["J\u00e1nos Bolyai Research Scholarship"]}],"id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]},{"name":"New National Excellence Program of the Ministry for Innovation and Technology","award":["\u00daNKP-20-5-DE-48"],"award-info":[{"award-number":["\u00daNKP-20-5-DE-48"]}]},{"name":"New National Excellence Program of the Ministry for Innovation and Technology","award":["\u00daNKP-20-3-I"],"award-info":[{"award-number":["\u00daNKP-20-3-I"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Correlative studies of clinical studies for hematological malignancies have implicated that less differentiated, CD8+-dominant CAR T cell products have greater antitumor activity. Here, we have investigated whether the differentiation status of CAR T cell products affects their antitumor activity in preclinical models of solid tumors. We explored if different activation\/expansion protocols, as well as different co-stimulatory domains in the CAR construct, influence the short- and long-term efficacy of CAR T cells against HER2-positive tumors. We generated T cell products that range from the most differentiated (CD28.z; OKT3-antiCD28\/RPMI expansion) to the least differentiated (41BB.z; OKT3-RetroNectin\/LymphoONE expansion), as judged by cell surface expression of the differentiation markers CCR7 and CD45RA. While the effect of differentiation status was variable with regard to antigen-specific cytokine production, the most differentiated CD28.z CAR T cell products, which were enriched in effector memory T cells, had the greatest target-specific cytolytic activity in vitro. These products also had a greater proliferative capacity and maintained CD4+ T cells upon repeated stimulation in vitro. In vivo, differentiated CD28.z CAR T cells also had the greatest antitumor activity, resulting in complete response. Our results highlight that it is critical to optimize CAR T cell production and that optimal product characteristics might depend on the targeted antigen and\/or cancer.<\/jats:p>","DOI":"10.3390\/cancers13174301","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T09:27:57Z","timestamp":1629970077000},"page":"4301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7442-0794","authenticated-orcid":false,"given":"Marianna","family":"Csapl\u00e1r","sequence":"first","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos","family":"Sz\u00f6ll\u0151si","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Gottschalk","sequence":"additional","affiliation":[{"name":"Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-3265","authenticated-orcid":false,"given":"Gy\u00f6rgy","family":"Vereb","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1rp\u00e1d","family":"Sz\u00f6\u0151r","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1073\/pnas.90.2.720","article-title":"Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors","volume":"90","author":"Eshhar","year":"1993","journal-title":"Proc. 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