{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:24:42Z","timestamp":1792549482826,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000},"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:p>Clinical applications of CAR-T cells are limited by the scarcity of tumor-specific targets and are often afflicted with the same on-target\/off-tumor toxicities that plague other cancer treatments. A new promising strategy to enforce tumor selectivity is the use of logic-gated, two-receptor systems. One well-described application is termed Tmod\u2122, which originally utilized a blocking inhibitory receptor directed towards HLA-I target antigens to create a protective NOT gate. Here we show that the function of Tmod blockers targeting non-HLA-I antigens is dependent on the height of the blocker antigen and is generally compatible with small, membrane-proximal targets. We compensate for this apparent limitation by incorporating modular hinge units to artificially extend or retract the ligand-binding domains relative to the effector cell surface, thereby modulating Tmod activator and blocker function. By accounting for structural differences between activator and blocker targets, we developed a set of simple geometric parameters for Tmod receptor design that enables targeting of blocker antigens beyond HLA-I, thereby broadening the applications of logic-gated cell therapies.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1304765","type":"journal-article","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T04:22:28Z","timestamp":1706242948000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Geometric parameters that affect the behavior of logic-gated CAR T cells"],"prefix":"10.3389","volume":"15","author":[{"given":"Alexander C.","family":"Partin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richele","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanam","family":"Shafaattalab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Vander Mause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Winters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Daris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey","family":"Gahrs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia A.","family":"Jette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Breanna","family":"DiAndreth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark L.","family":"Sandberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes E.","family":"Hamburger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kamb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P.","family":"Riley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1177\/1060028015588555","article-title":"Blinatumomab: A first-in-class bispecific T-cell engager for precursor B-cell acute lymphoblastic leukemia","volume":"49","author":"Buie","year":"2015","journal-title":"Ann Pharmacother"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4967","article-title":"Adoptive cell transfer as personalized immunotherapy for human cancer","volume":"348","author":"Rosenberg","year":"2015","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-062315-120245","article-title":"CAR T cell therapy for solid tumors","volume":"68","author":"Newick","year":"2017","journal-title":"Annu Rev Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"109030","DOI":"10.1016\/j.clim.2022.109030","article-title":"The Tmod cellular logic gate as a solution for tumor-selective immunotherapy","volume":"241","author":"DiAndreth","year":"2022","journal-title":"Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-004185","article-title":"To go or not to go? 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