{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:03:32Z","timestamp":1793106212490,"version":"4.5.0"},"reference-count":80,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Jiangsu Provincial Natural Science Major Project","award":["BK20222008"],"award-info":[{"award-number":["BK20222008"]}]},{"name":"Jiangsu Provincial Natural Science Major Project","award":["BM2023004"],"award-info":[{"award-number":["BM2023004"]}]},{"name":"CAST Young Scientist Program","award":["YESS20210160"],"award-info":[{"award-number":["YESS20210160"]}]},{"name":"Nanjing Medical University Career Development Fund","award":["NMUR20210006"],"award-info":[{"award-number":["NMUR20210006"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204545"],"award-info":[{"award-number":["82204545"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,9,18]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chimeric antigen receptor (CAR)-T cell therapy represents an innovative and potentially revolutionary modality in cancer treatment. Despite their great success in treating blood cancers, CAR-T therapies exhibit significantly lower effectiveness in treating solid tumors. Moreover, the preclinical-to-clinical translation of CAR-T therapies targeting solid tumors is still a challenging task because of their unique \u201clive cell\u201d nature and the substantial variability in patients\u2019 pathophysiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We have developed a multiscale quantitative systems pharmacology (QSP) model to facilitate the clinical translation of CAR-T therapies in solid tumors. Our mechanistic modeling framework integrates the essential biological features that impact CAR-T cell fate and antitumor cytotoxicity, from cell-level CAR-antigen interaction and activation, to in vivo CAR-T biodistribution, proliferation and phenotype transition, and finally to clinical-level patient tumor heterogeneity and response variability. This modeling framework has been calibrated and validated by multimodal experimental data including published preclinical and clinical data of various CAR-T products and original preclinical data of a novel claudin18.2-targeted CAR-T product LB1908.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrated the general utility of this framework in facilitating clinical translation and characterizing the paired cellular kinetics-cytotoxicity response of different antigen-targeting solid tumor CAR-T cell therapies. As an example, we generated model-based virtual patients and prospectively simulated the response to claudin18.2-targeted CAR-T therapies under different dosing strategies, including step-fractionated dosing and convenient flat dose-based regimens, to inform future clinical trial implementation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our translational QSP platform offers an innovative pathway to integrate multiscale knowledge and inform clinical decision-making of novel solid tumor-targeting CAR-T therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012331","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T12:10:16Z","timestamp":1760011816000},"page":"e012331","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Mechanistic data-informed multiscale quantitative systems pharmacology modeling framework enables the clinical translation and efficacy assessment of CAR-T therapy in solid tumors"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct01935843","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01869166","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03874897","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04581473","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Siyuan","family":"Yang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Legend Biotech, Nanjing, Jiangsu, 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