{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:35:55Z","timestamp":1789014955412,"version":"build-2803163510"},"reference-count":18,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"unspecified","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006379","name":"Office of Research and Development","doi-asserted-by":"publisher","award":["I01BX006247"],"award-info":[{"award-number":["I01BX006247"]}],"id":[{"id":"10.13039\/100006379","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031022","name":"Center for Cancer Research","doi-asserted-by":"publisher","award":["U54CA244711"],"award-info":[{"award-number":["U54CA244711"]}],"id":[{"id":"10.13039\/100031022","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,12,19]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Current second-generation CAR T cell products rely on CD28 or 4-1BB costimulatory domains, additions that respectively favor rapid cytolysis or long-term persistence, but rarely both. Preclinical modeling and retrospective analysis have linked CD2\u2013CD58 engagement to superior preclinical and clinical responses, yet the direct contribution of CD2 intracellular signaling remains undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We replaced the costimulatory domain of anti-mesothelin (SS1) and anti-TnMUC1 (5E5) CARs with the human CD2 cytoplasmic tail (CD2z) and benchmarked them against 28z and BBz formats. Transient mRNA expression was used to profile proximal Ca\n                      <jats:sup>2+<\/jats:sup>\n                      flux and degranulation free of tonic viral signals; durable functional assays employed lentiviral CARs. Cytokine release, genome-wide transcriptional programs, and anti-tumor activity were assessed in vitro and in NSG xenograft models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CD2z CAR T cells degranulated as efficiently as other z-containing CARs and generated a Ca\n                      <jats:sup>2+<\/jats:sup>\n                      flux signal intermediate to 28z and BBz CARs. Lentiviral CD2z CARs released a Th1-skewed cytokine panel and matched 28z cytolysis despite a lower acute cytokine release. Transcriptomic analysis characterized CD2z cells in an early effector-memory state: glycolytic, mTORC1, and TNFa\u2013NF-\u03baB hallmarks were upregulated, whereas exhaustion-up signatures were selectively depleted vs 28z. In vivo, a single CD2z infusion induced deep and durable tumor regressions over the 60-day observation period in subcutaneous mesothelin-positive mesothelioma and orthotopic TnMUC1-positive pancreatic tumor models, achieving tumor control comparable to 28z and more rapid early tumor clearance than BBz, while supporting peripheral T cell persistence similar to BBz.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The CD2 cytoplasmic tail, in combination with CD3z, delivers balanced costimulation that couples brisk tumor debulking to T cell persistence. CD2z therefore may provide a simple, versatile alternative to canonical CD28 and 4-1BB modules for next-generation CAR T therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013208","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T14:25:17Z","timestamp":1769091917000},"page":"e013208","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence"],"prefix":"10.1136","volume":"14","author":[{"given":"Fang","family":"Liu","sequence":"first","affiliation":[{"name":"Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T","family":"Keane","sequence":"additional","affiliation":[{"name":"Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon S","family":"Lewis","sequence":"additional","affiliation":[{"name":"Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany R","family":"King-Peoples","sequence":"additional","affiliation":[{"name":"Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl H","family":"June","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8711-629X","authenticated-orcid":false,"given":"Avery D","family":"Posey","sequence":"additional","affiliation":[{"name":"Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"},{"name":"Corporal Michael J Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"2026012206250801000_14.1.e013208.1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nature22395","article-title":"Therapeutic T cell engineering","volume":"545","author":"Sadelain","year":"2017","journal-title":"Nature New Biol"},{"key":"2026012206250801000_14.1.e013208.2","doi-asserted-by":"crossref","DOI":"10.1172\/JCI159402","article-title":"Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses","volume":"132","author":"Romain","year":"2022","journal-title":"J Clin Invest"},{"key":"2026012206250801000_14.1.e013208.3","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nature23477","article-title":"Identification of essential genes for cancer immunotherapy","volume":"548","author":"Patel","year":"2017","journal-title":"Nature New Biol"},{"key":"2026012206250801000_14.1.e013208.4","doi-asserted-by":"crossref","first-page":"100256","DOI":"10.1016\/j.modpat.2023.100256","article-title":"Detection of Aberrant CD58 Expression in a Wide Spectrum of Lymphoma Subtypes: Implications for Treatment Resistance","volume":"36","author":"Younes","year":"2023","journal-title":"Mod Pathol"},{"key":"2026012206250801000_14.1.e013208.5","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2216352120","article-title":"Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors","volume":"120","author":"Burton","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026012206250801000_14.1.e013208.6","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2011.192"},{"key":"2026012206250801000_14.1.e013208.7","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/s41423-025-01314-6","article-title":"CD2 augmentation enhances CAR-T-cell efficacy via immunological synapse remodeling and T-cell exhaustion mitigation","volume":"22","author":"Zhu","year":"2025","journal-title":"Cell Mol Immunol"},{"key":"2026012206250801000_14.1.e013208.8","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/nature14468","article-title":"T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection","volume":"523","author":"McKinney","year":"2015","journal-title":"Nature New Biol"},{"key":"2026012206250801000_14.1.e013208.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.2899908"},{"key":"2026012206250801000_14.1.e013208.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813101106"},{"key":"2026012206250801000_14.1.e013208.11","first-page":"9","article-title":"Measurement of intracellular ions by flow cytometry","volume":"72","author":"Posey","year":"2015","journal-title":"Curr Protoc Cytom"},{"key":"2026012206250801000_14.1.e013208.12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae410"},{"key":"2026012206250801000_14.1.e013208.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.09.006"},{"key":"2026012206250801000_14.1.e013208.14","doi-asserted-by":"publisher","DOI":"10.1038\/ng0506-500"},{"key":"2026012206250801000_14.1.e013208.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.021"},{"key":"2026012206250801000_14.1.e013208.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.05.014"},{"key":"2026012206250801000_14.1.e013208.17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133215"},{"key":"2026012206250801000_14.1.e013208.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0010-1"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-013208","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T14:25:18Z","timestamp":1769091918000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-013208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":18,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,22]]},"published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1136\/jitc-2025-013208"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-013208","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]}}}