{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:10:32Z","timestamp":1778821832102,"version":"3.51.4"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Adoptive cell therapy (ACT) using TCR-engineered T (TCR-T) cells is a promising strategy for treating solid tumors. One factor that influences the efficacy of ACT is the type of T cells used, with T cells displaying younger, less differentiated or tissue resident phenotypes associated with greater antitumor activity. We aimed to develop a rapid, clinical-scale protocol to generate younger and more potent TCR-T cells for therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Patient-derived PBMC were stimulated, CD8+ enriched, retrovirally transduced to express KRAS G12D-targeting TCRs, and expanded for 10 days in the presence of a novel cytokine cocktail (CKT) containing IL-2, IL-7, IL-15, and TGF-\u03b2. The impact of CKT on the phenotype, effector function, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      antitumor activity was evaluated and compared to TCR-T cells manufactured with IL-2. This process was then adapted for clinical-scale manufacturing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TCR-T cells generated with CKT displayed an increased frequency of early memory (Tn\/scm) and tissue-resident (Trm)-like T cells with decreased KLRG1 expression compared to IL-2 manufactured TCR-T cells. CKT manufactured TCR-T cells demonstrated higher 4-1BB upregulation, IFN-\u03b3, TNF, and granzyme B (GZMB) production, and enhanced killing of pancreatic and colorectal cancer cell lines in 2D and 3D tumor spheroid co-culture. Clinical-scale engineering runs yielded 3.30 and 6.15 x 10\n                      <jats:sup>9<\/jats:sup>\n                      total cells that displayed similar phenotypic and functional attributes observed in the small-scale studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our novel 10-day TCR-T manufacturing protocol using IL-2, IL-7, IL-15, and TGF-\u03b2 generates TCR-T cells characterized by distinct memory and tissue residency markers such as CCR7, CD103, and CD49a, and potent effector functions with the potential to improve the efficacy of adoptive cell therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1847411","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:26:51Z","timestamp":1778819211000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical-scale 10-day TCR-T cell manufacturing using IL-2\/7\/15 and TGF-\u03b2 promotes early memory and tissue-resident-like phenotypes and robust antitumor activity in vitro"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi-Ping","family":"Shih","sequence":"first","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Drokin","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Burke","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huayu","family":"Huang","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Leung","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Bravo-Manriquez","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myungkyu","family":"Jang","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina S.","family":"Syrkina","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Julian","sequence":"additional","affiliation":[{"name":"Earle A. Chiles Research Institute, a division of Providence Cancer Institute","place":["Portland, OR, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelson","family":"Sanjuan","sequence":"additional","affiliation":[{"name":"Earle A. 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