{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:22:30Z","timestamp":1787638950318,"version":"build-2736575974"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"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>Introduction<\/jats:title>\n                    <jats:p>Cytokines used during chimeric antigen receptor (CAR) T-cell manufacturing can influence product differentiation and functional fitness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated whether adding IL-21 to an IL-7 + IL-15 expansion regimen modulates CD84-directed CAR T cells (CART84) targeting CD84\n                      <jats:sup>+<\/jats:sup>\n                      acute myeloid leukemia (AML), using IL-7 + IL-15 alone as the primary comparator and IL-2 as a preclinical benchmark.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In healthy donor-derived CART84 cells, IL-21 supplementation was linked to an enrichment of less differentiated T-cell subsets, increased LAG-3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell frequency, enhanced expansion following repeated antigen stimulation, and increased CAR expression under G-Rex-based expansion conditions more closely resembling GMP-compatible manufacturing. However, these effects were not accompanied by consistent improvements in cytotoxicity or sustained tumor control upon serial rechallenge\n                      <jats:italic>in vitro<\/jats:italic>\n                      . In AML patient-derived CART84 cells, IL-21 supplementation did not confer a clear advantage in expansion, T-cell memory phenotype, or cytotoxic activity. Furthermore, IL-21 did not enhance CART84 efficacy or persistence in a MOLM-13 AML xenograft model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Overall, our results do not support routine incorporation of IL-21 into IL-7 + IL-15-based CART84 manufacturing protocols and highlight the need to evaluate cytokine supplementation strategies within the context of each CAR construct and disease setting.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1819376","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:34:31Z","timestamp":1787636071000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of IL-21 on CAR T-cell manufacturing: phenotypic, metabolic, and functional 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