{"title":"Mechanistic Evaluation of Anti-CD19 CAR-T Cell Therapy Repurposed in Systemic Lupus Erythematosus Using a Quantitative Systems Pharmacology Model","authors":"Hyunseo Park, Ganesh M. Mugundu, Aman P. Singh","doi":"10.1111/cts.70146","DOIUrl":null,"url":null,"abstract":"<p>CAR-T cell therapy, renowned for its success in oncology, is now venturing into the realm of B cell-mediated autoimmune diseases. Recent observations have revealed significant pharmacological effects of CD19 CAR-T cells in patients with systemic lupus erythematosus (SLE), suggesting promising applications in other autoimmune conditions. Consequently, as of December 2024, there are 116 different clinical trials evaluating CAR-T cells against autoimmune conditions. While the field is starting to understand the overall pharmacological actions of CAR-T cells in autoimmune diseases, the dose-exposure-response relationship remains inadequately characterized due to limited clinical data. To address these uncertainties, we have developed a Quantitative Systems Pharmacology (QSP) model using short-term limited clinical data of anti-CD19 CAR-Ts in autoimmune disease patients (<i>n</i> = 5), followed by a model qualification step utilizing an external dataset (<i>n</i> = 13). The developed QSP model integrated and effectively characterized the (1) cellular kinetics of different immunophenotypic population of CAR-T cells, (2) impact of lymphodepletion chemotherapy on host immune cells, (3) CAR-mediated elimination of CD19+ B-cells and (4) dynamic changes in disease surrogate biomarkers and its relationship with clinical score. The key pharmacological biomarkers which were incorporated within the QSP model included anti double stranded DNA (anti-dsDNA) antibodies, proteinuria, C3 protein and IFN-alpha. Later, a linear regression analysis-based relationship was developed between continuous disease biomarkers and the categorical SLE disease activity index (SLE-DAI) determined by the investigators offering a predictive framework for disease progression in SLE patients. This proposed QSP model holds potential to elucidate quantitative pharmacology and expedite clinical advancement of autologous and allogeneic cell therapies in autoimmune diseases.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 2","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70146","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cts-Clinical and Translational Science","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cts.70146","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
CAR-T cell therapy, renowned for its success in oncology, is now venturing into the realm of B cell-mediated autoimmune diseases. Recent observations have revealed significant pharmacological effects of CD19 CAR-T cells in patients with systemic lupus erythematosus (SLE), suggesting promising applications in other autoimmune conditions. Consequently, as of December 2024, there are 116 different clinical trials evaluating CAR-T cells against autoimmune conditions. While the field is starting to understand the overall pharmacological actions of CAR-T cells in autoimmune diseases, the dose-exposure-response relationship remains inadequately characterized due to limited clinical data. To address these uncertainties, we have developed a Quantitative Systems Pharmacology (QSP) model using short-term limited clinical data of anti-CD19 CAR-Ts in autoimmune disease patients (n = 5), followed by a model qualification step utilizing an external dataset (n = 13). The developed QSP model integrated and effectively characterized the (1) cellular kinetics of different immunophenotypic population of CAR-T cells, (2) impact of lymphodepletion chemotherapy on host immune cells, (3) CAR-mediated elimination of CD19+ B-cells and (4) dynamic changes in disease surrogate biomarkers and its relationship with clinical score. The key pharmacological biomarkers which were incorporated within the QSP model included anti double stranded DNA (anti-dsDNA) antibodies, proteinuria, C3 protein and IFN-alpha. Later, a linear regression analysis-based relationship was developed between continuous disease biomarkers and the categorical SLE disease activity index (SLE-DAI) determined by the investigators offering a predictive framework for disease progression in SLE patients. This proposed QSP model holds potential to elucidate quantitative pharmacology and expedite clinical advancement of autologous and allogeneic cell therapies in autoimmune diseases.
期刊介绍：
Clinical and Translational Science (CTS), an official journal of the American Society for Clinical Pharmacology and Therapeutics, highlights original translational medicine research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease. Translational medicine is a multi-faceted discipline with a focus on translational therapeutics. In a broad sense, translational medicine bridges across the discovery, development, regulation, and utilization spectrum. Research may appear as Full Articles, Brief Reports, Commentaries, Phase Forwards (clinical trials), Reviews, or Tutorials. CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine. Best-in-class methodologies and best practices are also welcomed as Tutorials. These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science. CTS welcomes high quality, scientifically sound, original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of both traditional drugs and innovative modalities.
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