{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:46Z","timestamp":1790920546816,"version":"4.1.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"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>Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell malignancies. However, strategies that improve the modularity and controllability of CAR signaling could broaden its applicability and safety across additional clinical contexts. Here, we describe a regulable CAR T-cell platform based on split intein-mediated protein trans-splicing (PTS) to conditionally reconstitute functional receptors in primary T-cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      As a proof of concept, we engineered a split CAR targeting CD1a (NCT05679895), a surface antigen expressed in T-cell acute lymphoblastic leukemia (T-ALL). The system consists of a membrane-anchored C-terminal scaffold containing the IMPDH.1\n                      <jats:sup>C<\/jats:sup>\n                      split intein fused to 4-1BB and CD3\u03b6 signaling domains, and a soluble N-terminal adaptor composed of an anti-CD1a single-chain variable fragment (scFv) fused to the complementary IMPDH.1\n                      <jats:sup>N<\/jats:sup>\n                      split intein.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Upon delivery of the adaptor module, the intein fragments undergo PTS, generating a functional membrane-bound CD1a CAR with splicing efficiencies of 85%. Reconstituted CAR T-cells exhibited antigen-specific cytotoxicity against CD1a\n                      <jats:sup>+<\/jats:sup>\n                      T-ALL cells coupled to high levels of interferon-\u03b3 secretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that split intein-mediated CAR reconstitution enables a modular platform for conditional CAR reconstitution and transient control of receptor availability.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1844972","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:37:42Z","timestamp":1790919462000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Split intein-mediated reconstitution of regulatable CAR T-cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Vladimir","family":"Mulens-Arias","sequence":"first","affiliation":[{"name":"Josep Carreras Leukemia Research Institute (IJC)","place":["Barcelona, Spain"]},{"name":"Red Espa\u00f1ola de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Archinti","sequence":"additional","affiliation":[{"name":"ZIP Solutions SL.","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Bastida","sequence":"additional","affiliation":[{"name":"ZIP Solutions SL.","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"ZIP Solutions SL.","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, Universityof Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor M.","family":"D\u00edaz","sequence":"additional","affiliation":[{"name":"OneChain Immunotherapeutics SL.","place":["Barcelona, Spain"]},{"name":"Universitat Internacional de Catalunya","place":["Sant Cugat del Vall\u00e8s, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Men\u00e9ndez","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukemia Research Institute (IJC)","place":["Barcelona, Spain"]},{"name":"Red Espa\u00f1ola de Terapias Avanzadas (TERAV+), Instituto de Salud Carlos III","place":["Madrid, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC)","place":["Madrid, Spain"]},{"name":"Department of Biomedicine, School of Medicine, University of Barcelona","place":["Barcelona, Spain"]},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats (ICREA)","place":["Barcelona, Spain"]},{"name":"Institut de Recerca Hospital Sant Joan de D\u00e9u-Pediatric Cancer Center Barcelona (SJD-PCCB)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1288383","article-title":"CAR-T treatment for cancer: prospects and challenges","volume":"13","author":"Chen","year":"2023","journal-title":"Front Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.3390\/cancers17183027","article-title":"CAR-T cell therapies in B-cell acute lymphoblastic leukemia: Emerging data and open 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