{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:55:25Z","timestamp":1788324925097,"version":"build-2803163510"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Chimeric Antigen Receptor (CAR) T-cell therapies have emerged as an effective and potentially curative immunotherapy for patients with relapsed or refractory malignancies. Treatment with CD19 CAR T-cells has shown unprecedented results in hematological malignancies, including heavily refractory leukemia, lymphoma, and myeloma cases. Despite these encouraging results, CAR T-cell therapy faces limitations, including the lack of long-term responses in nearly 50-70% of the treated patients and low efficacy in solid tumors. Among other reasons, these restrictions are related to the lack of targetable tumor-associated antigens, limitations on the CAR design and interactions with the tumor microenvironment (TME), as well as short-term CAR T-cell persistence. Because of these reasons, we developed and tested a chimeric antigen receptor (CAR) construct with an anti-ROR1 single-chain variable-fragment cassette connected to CD3\u03b6 by second and third-generation intracellular signaling domains including 4-1BB, CD28\/4-1BB, ICOS\/4-1BB or ICOS\/OX40. We observed that after several successive tumor-cell <jats:italic>in vitro<\/jats:italic> challenges, ROR1.ICOS.OX40\u03b6 continued to proliferate, produce pro-inflammatory cytokines, and induce cytotoxicity against ROR1<jats:sup>+<\/jats:sup> cell lines <jats:italic>in vitro<\/jats:italic> with enhanced potency. Additionally, <jats:italic>in vivo<\/jats:italic> ROR1.ICOS.OX40\u03b6 T-cells showed anti-lymphoma activity, a long-lasting central memory phenotype, improved overall survival, and evidence of long-term CAR T-cell persistence. We conclude that anti-ROR1 CAR T-cells that are activated by ICOS.OX40 tandem co-stimulation show <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> enhanced targeted cytotoxicity associated with a phenotype that promotes T-cell persistence.<\/jats:p>","DOI":"10.3389\/fonc.2023.1200914","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T11:16:54Z","timestamp":1692357414000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["ICOS and OX40 tandem co-stimulation enhances CAR T-cell cytotoxicity and promotes T-cell persistence phenotype"],"prefix":"10.3389","volume":"13","author":[{"given":"Eider","family":"Moreno-Cortes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Franco-Fuquen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan 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