{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:32:42Z","timestamp":1792647162027,"version":"4.5.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    T cells expressing a mesothelin (MSLN)-specific T cell receptor fusion construct (TRuC\n                    <jats:sup>\u00ae<\/jats:sup>\n                    ), called TC-210, have demonstrated robust antitumor activity in preclinical models of mesothelioma, ovarian cancer, and lung cancer. However, they are susceptible to suppression by the programmed cell death protein 1 (PD-1)\/programmed cell death protein ligand 1 (PD-L1) axis and lack intrinsic costimulatory signaling elements. To enhance the function of anti-MSLN TRuC-T cells, chimeric switch receptors (CSRs) have been designed to co-opt the immunosuppressive PD-1\/PD-L1 axis and to deliver a CD28-mediated costimulatory signal. Here, we report that coexpression of the PD1-CD28 CSR in TRuC-T cells enhanced T cell receptor signaling, increased proinflammatory effector cytokines, decreased anti-inflammatory cytokines, and sustained effector function in the presence of PD-L1 when compared with TC-210. Anti-MSLN TRuC-T cells engineered to coexpress PD1-CD28 CSRs comprising the ectodomain of PD-1 and the intracellular domain of CD28 linked by the transmembrane domain of PD-1 were selected for integration into an anti-MSLN TRuC-T cell therapy product called TC-510. In vitro, TC-510 showed significant improvements in persistence and resistance to exhaustion upon chronic stimulation by tumor cells expressing MSLN and PD-L1 when compared with TC-210. In vivo, TC-510 showed a superior ability to provide durable protection following tumor rechallenge, versus TC-210. These data demonstrate that integration of a PD1-CD28 CSR into TRuC-T cells improves effector function, resistance to exhaustion, and prolongs persistence. Based on these findings, TC-510 is currently being evaluated in patients with MSLN-expressing solid tumors.\n                  <\/jats:p>","DOI":"10.1007\/s00262-023-03556-7","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T22:01:48Z","timestamp":1697580108000},"page":"4195-4207","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Functional enhancement of mesothelin-targeted TRuC-T cells by a PD1-CD28 chimeric switch receptor"],"prefix":"10.1007","volume":"72","author":[{"given":"Derrick","family":"McCarthy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lofgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Watt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Horton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Kieffer-Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Kobold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick A.","family":"Baeuerle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hofmeister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario A.","family":"Gutierrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Tighe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"key":"3556_CR1","doi-asserted-by":"publisher","first-page":"2182058","DOI":"10.1080\/2162402X.2023.2182058","volume":"12","author":"J Ding","year":"2023","unstructured":"Ding J, Guyette S, Schrand B et al (2023) Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors. 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RT is a current employee of Ankyra Therapeutics. ML and AW are current employees of Adaptimmune, which acquired TCR<sup>2<\/sup> Therapeutics. JD is a current employee of Myeloid Therapeutics. SK is an inventor of several patents in the field of immuno-oncology, has received honoraria from BMS, GSK, Novartis, TCR<sup>2<\/sup> Therapeutics, and Miltenyi Biomedicine, received license fees from Carina Biotech and TCR<sup>2<\/sup> Therapeutics, and received research support from TCR<sup>2<\/sup> Therapeutics for work related to this manuscript and from Arcus Bioscience, Plectonic GmbH, and Tabby Therapeutics for work unrelated to the manuscript. SK is a former shareholder of TCR<sup>2<\/sup> Therapeutics, and a current shareholder of Adaptimmune. PAB is a shareholder, scientific advisor, and founder of TCR<sup>2<\/sup> Therapeutics. RH is a former employee and shareholder of TCR<sup>2<\/sup> Therapeutics, and a current shareholder of Adaptimmune. DAG is a shareholder at TCR<sup>2<\/sup> Therapeutics. No competing interests were disclosed by DM, HH and PK-K.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Consent for publication is not required for these preclinical studies.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All animal studies were approved by the Institutional Animal Care and Use Committee of Charles River Laboratories under protocol 2021-1261. Human T cells used in these studies were sourced commercially from healthy volunteer donors.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}