{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:52:20Z","timestamp":1791219140286,"version":"4.1.0"},"reference-count":89,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T00:00:00Z","timestamp":1696550400000},"content-version":"unspecified","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016947","name":"Swim Across America","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100016947","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K08CA252642"],"award-info":[{"award-number":["K08CA252642"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["NCI-5K23CA178083"],"award-info":[{"award-number":["NCI-5K23CA178083"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["NCI-F31CA250320"],"award-info":[{"award-number":["NCI-F31CA250320"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30 CA076292"],"award-info":[{"award-number":["P30 CA076292"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Turnstone Biologics, Inc.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-16- 117-01-LIB"],"award-info":[{"award-number":["RSG-16- 117-01-LIB"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. Adelson Medical Research Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,9,13]]},"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4<jats:sup>+<\/jats:sup>T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We discovered that neoantigen-specific TIL clones were predominantly CD4<jats:sup>+<\/jats:sup> T cells and were present in both therapeutic responders and non-responders. CD4<jats:sup>+<\/jats:sup> TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4<jats:sup>+<\/jats:sup> TIL.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4<jats:sup>+<\/jats:sup> T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4<jats:sup>+<\/jats:sup> TIL in future ACT protocols as a strategy to improve antitumor immunity.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-007288","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T11:38:21Z","timestamp":1707478701000},"page":"e007288","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Neoantigen-specific CD4<sup>+<\/sup> tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct01005745","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01701674","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01659151","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05628883","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5626-1619","authenticated-orcid":false,"given":"MacLean S.","family":"Hall","sequence":"first","affiliation":[{"name":"Department of Immunology, H. 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