{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T13:51:23Z","timestamp":1793195483229,"version":"4.5.0"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"22","license":[{"start":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T00:00:00Z","timestamp":1732233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01CA254035"],"award-info":[{"award-number":["R01CA254035"]}]},{"name":"National Institute of Health","award":["R21CA292224"],"award-info":[{"award-number":["R21CA292224"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,22]]},"abstract":"<jats:p>\n                    The application of chimeric antigen receptor (CAR) T cell therapy in solid tumors is hindered by life-threatening toxicities resulting from on-target, off-tumor killing of nonmalignant cells that express low levels of the target antigen. Mesothelin (MSLN) has been identified as a target antigen for CAR T cell treatment of mesothelioma, lung, ovarian, and other cancers because of its high expression on tumor cells and limited expression on mesothelial cells. However, fatal off-tumor toxicity of high-affinity MSLN-targeting CAR T cells has been reported in multiple clinical trials. In this study, we constructed CARs using mutant variants of a single-domain nanobody that bind both human and mouse MSLN with a wide range of affinities and examined tumor responses and their toxicities from on-target, off-tumor interactions in mouse models. CAR T cells with low nanomolar affinity (equilibrium dissociation constant,\n                    <jats:italic>\n                      K\n                      <jats:sub>D<\/jats:sub>\n                    <\/jats:italic>\n                    ) exhibited profound systemic expansion with no apparent infiltration into the tumor. With a gradual reduction of CAR affinity toward the micromolar\n                    <jats:italic>\n                      K\n                      <jats:sub>D<\/jats:sub>\n                    <\/jats:italic>\n                    , the expansion of CAR T cells became more restricted to tumors. Our preclinical studies demonstrated that high-affinity MSLN CARs were associated with fatal on-target, off-tumor toxicity and that affinity-tuned CARs rendered T cells more selective for MSLN-high tumors.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.186268","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T14:00:42Z","timestamp":1732197642000},"source":"Crossref","is-referenced-by-count":39,"title":["Affinity-tuned mesothelin CAR T cells demonstrate enhanced targeting specificity and reduced off-tumor toxicity"],"prefix":"10.1172","volume":"9","author":[{"given":"Yanping","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Radiology, Houston Methodist Research Institute, Houston, Texas, USA."},{"name":"Department of Radiology, Weill Cornell Medicine, New York, New York, 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