{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:25:44Z","timestamp":1792031144653,"version":"4.4.0"},"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Chimeric antigen receptor (CAR)-T cell therapy holds significant potential for cancer treatment, although disease relapse and cytokine release syndrome (CRS) remain as frequent clinical challenges. To better understand the mechanisms underlying the temporal dynamics of CAR-T cell therapy response and CRS, we developed a novel multi-layer mathematical model incorporating antigen-mediated CAR-T cell expansion, antigen-negative resistance, and macrophage-associated cytokine release. Three key mechanisms of macrophage activation are considered: release of damage-associated molecular patterns, antigen-binding mediated activation, and CD40-CD40L contact. The model accurately describes 25 patient time courses with different responses and IL-6 cytokine kinetics. We successfully link the dynamic shape of the response to interpretable model parameters and investigate the influence of CAR-T cell dose and initial tumor burden on the occurrence of cytokine release and treatment outcome. By disentangling the timeline of macrophage activation, the model identified distinct contributions of each activation mechanism, suggesting the CD40-CD40L axis as a major driver of cytokine release and a clinically feasible target to control the activation process and modulate cytokine peak height. Our multi-layer model provides a comprehensive framework for understanding the complex interactions between CAR-T cells, tumor cells, and macrophages during therapy.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012908","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T16:08:36Z","timestamp":1744214916000},"page":"e1012908","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome"],"prefix":"10.1371","volume":"21","author":[{"given":"Daniela S","family":"Santurio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana R C","family":"Barros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingmar","family":"Glauche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3634-0061","authenticated-orcid":true,"given":"Artur c","family":"Fassoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"issue":"16","key":"pcbi.1012908.ref001","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1056\/NEJMoa1215134","article-title":"Chimeric antigen receptor\u2013modified T cells for acute lymphoid leukemia","volume":"368","author":"SA Grupp","year":"2013","journal-title":"N Engl J Med"},{"issue":"11","key":"pcbi.1012908.ref002","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.3390\/cancers14112667","article-title":"Systematic review of available CAR-T cell trials around the world","volume":"14","author":"LRC Barros","year":"2022","journal-title":"Cancers (Basel)"},{"issue":"5","key":"pcbi.1012908.ref003","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/psp4.12388","article-title":"Tisagenlecleucel model-based cellular kinetic analysis of chimeric antigen receptor-T cells","volume":"8","author":"AM Stein","year":"2019","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"issue":"3","key":"pcbi.1012908.ref004","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/cpt.2040","article-title":"Model-based cellular kinetic analysis of chimeric antigen receptor-T cells in humans","volume":"109","author":"C Liu","year":"2021","journal-title":"Clin Pharmacol Ther"},{"issue":"22","key":"pcbi.1012908.ref005","doi-asserted-by":"crossref","first-page":"5576","DOI":"10.3390\/cancers14225576","article-title":"Modeling patient-specific CAR-T cell dynamics: multiphasic kinetics via phenotypic differentiation","volume":"14","author":"EA Paix\u00e3o","year":"2022","journal-title":"Cancers (Basel)"},{"issue":"6","key":"pcbi.1012908.ref006","first-page":"372","article-title":"Mechanisms of resistance to CAR T cell therapy","volume":"16","author":"N Shah","year":"2019","journal-title":"Nat Rev Clin Oncol."},{"key":"pcbi.1012908.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.apm.2023.08.029","article-title":"Mechanisms of resistance to CAR-T cell immunotherapy: Insights from a mathematical model","volume":"125","author":"DS Santurio","year":"2024","journal-title":"Appl Math Model"},{"issue":"2","key":"pcbi.1012908.ref008","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41577-021-00547-6","article-title":"Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy","volume":"22","author":"EC Morris","year":"2022","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"pcbi.1012908.ref009","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrclinonc.2017.148","article-title":"Chimeric antigen receptor T-cell therapy - assessment and management of toxicities","volume":"15","author":"SS Neelapu","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"pcbi.1012908.ref010"},{"key":"pcbi.1012908.ref011","doi-asserted-by":"crossref","first-page":"814548","DOI":"10.3389\/fimmu.2022.814548","article-title":"Correlation of cytokine release syndrome with prognosis after chimeric antigen receptor T cell therapy: analysis of 54 patients with relapsed or refractory multiple myeloma","volume":"13","author":"X Wang","year":"2022","journal-title":"Front Immunol"},{"issue":"1","key":"pcbi.1012908.ref012","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1097\/MOP.0000000000000043","article-title":"Toxicity management for patients receiving novel T-cell engaging therapies","volume":"26","author":"DM Barrett","year":"2014","journal-title":"Curr Opin Pediatr"},{"issue":"25","key":"pcbi.1012908.ref013","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1200\/JCO.19.03237","article-title":"Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia","volume":"38","author":"NV Frey","year":"2020","journal-title":"J Clin Oncol"},{"issue":"6","key":"pcbi.1012908.ref014","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/s41591-018-0041-7","article-title":"CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade","volume":"24","author":"T Giavridis","year":"2018","journal-title":"Nat Med"},{"issue":"6","key":"pcbi.1012908.ref015","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/s41591-018-0041-7","article-title":"CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade","volume":"24","author":"T Giavridis","year":"2018","journal-title":"Nat Med"},{"issue":"6","key":"pcbi.1012908.ref016","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/s41591-018-0036-4","article-title":"Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells","volume":"24","author":"M Norelli","year":"2018","journal-title":"Nat Med"},{"issue":"3","key":"pcbi.1012908.ref017","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s40324-022-00296-z","article-title":"Mathematical models of leukaemia and its treatment: a review","volume":"79","author":"S Chuli\u00e1n","year":"2022","journal-title":"SeMA J."},{"issue":"1947","key":"pcbi.1012908.ref018","first-page":"20210229","article-title":"The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy","volume":"288","author":"GJ Kimmel","year":"2021","journal-title":"Proc Biol Sci"},{"issue":"12","key":"pcbi.1012908.ref019","doi-asserted-by":"crossref","first-page":"6371","DOI":"10.3390\/ijms22126371","article-title":"A mathematical description of the bone marrow dynamics during CAR T-cell therapy in B-cell childhood acute lymphoblastic leukemia","volume":"22","author":"A P\u00e9rez-Mart\u00ednez","year":"2021","journal-title":"Int J Molecul Sci."},{"key":"pcbi.1012908.ref020","doi-asserted-by":"crossref","first-page":"1115536","DOI":"10.3389\/fimmu.2023.1115536","article-title":"Data driven model discovery and interpretation for CAR T-cell killing using sparse identification and latent variables","volume":"14","author":"AB Brummer","year":"2023","journal-title":"Front Immunol"},{"key":"pcbi.1012908.ref021","doi-asserted-by":"crossref","first-page":"105570","DOI":"10.1016\/j.cnsns.2020.105570","article-title":"CAR T cell therapy in B-cell acute lymphoblastic leukaemia: Insights from mathematical models","volume":"94","author":"O Leo\u00b4n-Triana","year":"2021","journal-title":"Commun Nonl Sci Numer Simulat"},{"issue":"4","key":"pcbi.1012908.ref022","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/cts.12636","article-title":"Quantitative systems pharmacology model of chimeric antigen receptor T-cell therapy","volume":"12","author":"D Hardiansyah","year":"2019","journal-title":"Clin Transl Sci"},{"issue":"1","key":"pcbi.1012908.ref023","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3934\/naco.2018004","article-title":"Mathematical model of chimeric anti-gene receptor (CAR) T cell therapy with presence of cytokine","volume":"8","author":"R Mostolizadeh","year":"2018","journal-title":"Numer Algebra Control Optimiz"},{"issue":"2","key":"pcbi.1012908.ref024","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00498-023-00362-5","article-title":"Cytokine storm mitigation for exogenous immune agonists","volume":"36","author":"I Kareva","year":"2023","journal-title":"Math Control Signals Syst"},{"issue":"10","key":"pcbi.1012908.ref025","doi-asserted-by":"crossref","first-page":"2200130","DOI":"10.1002\/adtp.202200130","article-title":"A computational model of cytokine release syndrome during CAR T-cell therapy","volume":"5","author":"Z Zhang","year":"2022","journal-title":"Adv Ther (Weinh)"},{"key":"pcbi.1012908.ref026","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jtbi.2012.12.025","article-title":"Quantifying T lymphocyte turnover","volume":"327","author":"RJ De Boer","year":"2013","journal-title":"J Theor Biol"},{"key":"pcbi.1012908.ref027"},{"issue":"12","key":"pcbi.1012908.ref028","doi-asserted-by":"crossref","first-page":"6371","DOI":"10.3390\/ijms22126371","article-title":"A mathematical description of the bone marrow dynamics during CAR T-cell therapy in B-cell childhood acute lymphoblastic leukemia","volume":"22","author":"A Mart\u00ednez-Rubio","year":"2021","journal-title":"Int J Molecul Sci."},{"key":"pcbi.1012908.ref029"},{"issue":"5","key":"pcbi.1012908.ref030","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.coi.2013.09.003","article-title":"Lineage relationship of effector and memory T cells","volume":"25","author":"NP Restifo","year":"2013","journal-title":"Curr Opin Immunol"},{"issue":"11","key":"pcbi.1012908.ref031","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.3390\/cancers13112782","article-title":"Early survival prediction framework in CD19-specific CAR-T cell immunotherapy using a quantitative systems pharmacology model","volume":"13","author":"A Mueller-Schoell","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"5","key":"pcbi.1012908.ref032","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1002\/hon.2672","article-title":"Evidence of long-lasting anti-CD19 activity of engrafted CD19 chimeric antigen receptor-modified T cells in a phase I study targeting pediatrics with acute lymphoblastic leukemia","volume":"37","author":"F Ma","year":"2019","journal-title":"Hematol Oncol"},{"issue":"6","key":"pcbi.1012908.ref033","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.3390\/ijms20061283","article-title":"Killing mechanisms of chimeric antigen receptor (CAR) T cells","volume":"20","author":"M-R Benmebarek","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"8","key":"pcbi.1012908.ref034","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1182\/bloodadvances.2020004038","article-title":"Absolute lymphocyte count proliferation kinetics after CAR T-cell infusion impact response and relapse","volume":"5","author":"S Faude","year":"2021","journal-title":"Blood Adv"},{"issue":"8","key":"pcbi.1012908.ref035","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1007\/s00277-018-3368-8","article-title":"The severe cytokine release syndrome in phase I trials of CD19-CAR-T cell therapy: a systematic review","volume":"97","author":"Z Jin","year":"2018","journal-title":"Ann Hematol"},{"issue":"1","key":"pcbi.1012908.ref036","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/s41392-020-00256-x","article-title":"The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma","volume":"5","author":"J Wei","year":"2020","journal-title":"Signal Transduct Target Ther"},{"issue":"21","key":"pcbi.1012908.ref037","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.3390\/cells12212581","article-title":"Cell-based models of \u201cCytokine release syndrome\u201d endorse CD40L and granulocyte-macrophage colony-stimulating factor knockout in chimeric antigen receptor T cells as mitigation strategy","volume":"12","author":"A Dibas","year":"2023","journal-title":"Cells"},{"issue":"3","key":"pcbi.1012908.ref038","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1182\/bloodadvances.2019000525","article-title":"Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed\/refractory DLBCL","volume":"4","author":"R Awasthi","year":"2020","journal-title":"Blood Adv"},{"issue":"3","key":"pcbi.1012908.ref039","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s40265-017-0690-8","article-title":"Chimeric Antigen Receptor (CAR) T cells: lessons learned from targeting of CD19 in B-cell malignancies","volume":"77","author":"KA Hay","year":"2017","journal-title":"Drugs"},{"issue":"22","key":"pcbi.1012908.ref040","doi-asserted-by":"crossref","first-page":"5607","DOI":"10.1182\/bloodadvances.2020003001","article-title":"Predictive factors of early progression after CAR T-cell therapy in relapsed\/refractory diffuse large B-cell lymphoma","volume":"4","author":"L Vercellino","year":"2020","journal-title":"Blood Adv"},{"key":"pcbi.1012908.ref041"},{"issue":"21","key":"pcbi.1012908.ref042","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1182\/blood-2017-06-793141","article-title":"Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy","volume":"130","author":"KA Hay","year":"2017","journal-title":"Blood"},{"issue":"8","key":"pcbi.1012908.ref043","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1007\/s00277-018-3368-8","article-title":"The severe cytokine release syndrome in phase I trials of CD19-CAR-T cell therapy: a systematic review","volume":"97","author":"Z Jin","year":"2018","journal-title":"Ann Hematol"},{"issue":"10","key":"pcbi.1012908.ref044","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1007\/s12325-019-01056-8","article-title":"Individual patient data meta-analysis from 16 trials for safety factors in cytokine release syndrome after CAR-T therapy in patients with Non-Hodgkin Lymphoma (NHL) and acute lymphoblastic Leukemia","volume":"36","author":"J Li","year":"2019","journal-title":"Adv Ther"},{"key":"pcbi.1012908.ref045","doi-asserted-by":"crossref","first-page":"713577","DOI":"10.3389\/fonc.2021.713577","article-title":"Tumor burden measured by 18F-FDG PET\/CT in predicting efficacy and adverse effects of chimeric antigen receptor T-cell therapy in Non-Hodgkin Lymphoma","volume":"11","author":"R Hong","year":"2021","journal-title":"Front Oncol"},{"issue":"23","key":"pcbi.1012908.ref046","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1182\/blood.V126.23.684.684","article-title":"Safety and response of incorporating CD19 chimeric antigen receptor T cell therapy in typical salvage regimens for children and young adults with acute lymphoblastic leukemia","volume":"126","author":"III Lee DW","year":"2015","journal-title":"Blood"},{"issue":"19","key":"pcbi.1012908.ref047","doi-asserted-by":"crossref","first-page":"4898","DOI":"10.1182\/bloodadvances.2020002394","article-title":"Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma","volume":"4","author":"FL Locke","year":"2020","journal-title":"Blood Adv"},{"issue":"19","key":"pcbi.1012908.ref048","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ifacol.2018.09.039","article-title":"A model-based investigation of cytokine storm for T-cell therapy","volume":"51","author":"B Hopkins","year":"2018","journal-title":"IFAC-PapersOnLine"},{"issue":"10","key":"pcbi.1012908.ref049","doi-asserted-by":"crossref","first-page":"e45027","DOI":"10.1371\/journal.pone.0045027","article-title":"Dynamics of a cytokine storm","volume":"7","author":"HH Yiu","year":"2012","journal-title":"PLoS One"},{"key":"pcbi.1012908.ref050","article-title":"Mathematical model of a cytokine storm","author":"I Kareva","year":"2022","journal-title":"bioRxiv"},{"key":"pcbi.1012908.ref051","doi-asserted-by":"crossref","first-page":"639423","DOI":"10.3389\/fmolb.2021.639423","article-title":"A validated mathematical model of the cytokine release syndrome in severe COVID-19","volume":"8","author":"RF Reis","year":"2021","journal-title":"Front Mol Biosci"},{"key":"pcbi.1012908.ref052","doi-asserted-by":"crossref","first-page":"814548","DOI":"10.3389\/fimmu.2022.814548","article-title":"Correlation of cytokine release syndrome with prognosis after chimeric antigen receptor T cell therapy: analysis of 54 patients with relapsed or refractory multiple myeloma","volume":"13","author":"X Wang","year":"2022","journal-title":"Front Immunol"},{"issue":"2","key":"pcbi.1012908.ref053","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nri1550","article-title":"The role of models in understanding CD8+ T-cell memory","volume":"5","author":"R Antia","year":"2005","journal-title":"Nat Rev Immunol"},{"issue":"22","key":"pcbi.1012908.ref054","doi-asserted-by":"crossref","first-page":"10663","DOI":"10.1128\/JVI.75.22.10663-10669.2001","article-title":"Recruitment times, proliferation, and apoptosis rates during the CD8(+) T-cell response to lymphocytic choriomeningitis virus","volume":"75","author":"RJ De Boer","year":"2001","journal-title":"J Virol"},{"issue":"3","key":"pcbi.1012908.ref055","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/bjh.15195","article-title":"Treatment of acute lymphoblastic leukaemia with the second generation of CD19 CAR-T containing either CD28 or 4-1BB","volume":"181","author":"S Li","year":"2018","journal-title":"Br J Haematol"},{"key":"pcbi.1012908.ref056"},{"key":"pcbi.1012908.ref057"},{"issue":"7","key":"pcbi.1012908.ref058","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1182\/bloodadvances.2019001304","article-title":"Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial","volume":"4","author":"SJ Schuster","year":"2020","journal-title":"Blood Adv"},{"issue":"4","key":"pcbi.1012908.ref059","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells","volume":"25","author":"DW Lee","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"issue":"1","key":"pcbi.1012908.ref060","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13045-018-0571-y","article-title":"Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel","volume":"11","author":"D Porter","year":"2018","journal-title":"J Hematol Oncol"},{"issue":"2","key":"pcbi.1012908.ref061","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1182\/blood-2014-05-552729","article-title":"Current concepts in the diagnosis and management of cytokine release syndrome","volume":"124","author":"DW Lee","year":"2014","journal-title":"Blood"},{"issue":"1","key":"pcbi.1012908.ref062","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1186\/s13046-021-02148-6","article-title":"Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies","volume":"40","author":"X Xiao","year":"2021","journal-title":"J Exp Clin Cancer Res"},{"issue":"8","key":"pcbi.1012908.ref063","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1634\/theoncologist.2018-0028","article-title":"FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome","volume":"23","author":"RQ Le","year":"2018","journal-title":"Oncologist"},{"key":"pcbi.1012908.ref064","doi-asserted-by":"crossref","first-page":"1422591","DOI":"10.3389\/fimmu.2024.1422591","article-title":"Systemic toxicity of CAR-T therapy and potential monitoring indicators for toxicity prevention","volume":"15","author":"J Li","year":"2024","journal-title":"Front Immunol"},{"key":"pcbi.1012908.ref065"},{"issue":"12","key":"pcbi.1012908.ref066","doi-asserted-by":"crossref","first-page":"e005360","DOI":"10.1136\/jitc-2022-005360","article-title":"Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse","volume":"10","author":"L Liu","year":"2022","journal-title":"J Immunother Cancer"},{"issue":"2","key":"pcbi.1012908.ref067","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41577-021-00547-6","article-title":"Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy","volume":"22","author":"EC Morris","year":"2022","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"pcbi.1012908.ref068","first-page":"1","article-title":"Haematology reference intervals for established and novel parameters in healthy adults","volume":"20","author":"J Pekelharing","year":"2010","journal-title":"Sysmex J Int."},{"issue":"9967","key":"pcbi.1012908.ref069","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0140-6736(14)61403-3","article-title":"T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial","volume":"385","author":"DW Lee","year":"2015","journal-title":"Lancet"},{"issue":"4","key":"pcbi.1012908.ref070","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1002\/psp4.12598","article-title":"Bench-to-bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic-pharmacodynamic model: a case study with anti-BCMA CAR-T","volume":"10","author":"AP Singh","year":"2021","journal-title":"CPT Pharmacomet Syst Pharmacol"},{"issue":"5","key":"pcbi.1012908.ref071","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11538-021-00869-5","article-title":"Modeling CAR T-cell therapy with patient preconditioning","volume":"83","author":"K Owens","year":"2021","journal-title":"Bull Math Biol"},{"issue":"6","key":"pcbi.1012908.ref072","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1634\/stemcells.22-6-1111","article-title":"Cell division rates of primary human precursor B cells in culture reflect in vivo rates","volume":"22","author":"J Cooperman","year":"2004","journal-title":"Stem Cells"},{"key":"pcbi.1012908.ref073","article-title":"QSP Designer: quantitative systems pharmacology modeling with modular biological process map notation and multiple language code generation","author":"RJ Matthews","year":"2023","journal-title":"CPT: Pharmacomet Syst Pharmacol"},{"issue":"44","key":"pcbi.1012908.ref074","doi-asserted-by":"crossref","first-page":"e2308511120","DOI":"10.1073\/pnas.2308511120","article-title":"The total mass, number, and distribution of immune cells in the human body","volume":"120","author":"R Sender","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pcbi.1012908.ref075","first-page":"121","article-title":"Properties of human blood monocytes","volume":"86","author":"D Hudig","year":"2014","journal-title":"II. Monocytes from healthy adults are highly heterogeneous within and among individuals. Cytometry B Clin Cytom"},{"issue":"2","key":"pcbi.1012908.ref076","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s40828-022-00163-4","article-title":"Macrophages: shapes and functions","volume":"8","author":"U Lendeckel","year":"2022","journal-title":"ChemTexts"},{"key":"pcbi.1012908.ref077","doi-asserted-by":"crossref","first-page":"111207","DOI":"10.1016\/j.jtbi.2022.111207","article-title":"Mathematical investigation into the role of macrophage heterogeneity on the temporal and spatio-temporal dynamics of non-small cell lung cancers","volume":"549","author":"L Bartha","year":"2022","journal-title":"J Theor Biol"},{"issue":"3","key":"pcbi.1012908.ref078","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1111\/imm.13320","article-title":"Monocytes, macrophages, dendritic cells and neutrophils: an update on lifespan kinetics in health and disease","volume":"163","author":"AA Patel","year":"2021","journal-title":"Immunology"},{"issue":"1","key":"pcbi.1012908.ref079","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12879-019-3800-2","article-title":"Is Interleukin-6 a better predictor of successful antibiotic therapy than procalcitonin and C-reactive protein? A single center study in critically ill adults","volume":"19","author":"L Weidhase","year":"2019","journal-title":"BMC Infect Dis"},{"issue":"2","key":"pcbi.1012908.ref080","doi-asserted-by":"crossref","first-page":"80","DOI":"10.5625\/lar.2018.34.2.80","article-title":"Elimination half-lives of interleukin-6 and cytokine-induced neutrophil chemoattractant-1 synthesized in response to inflammatory stimulation in rats","volume":"34","author":"T Kuribayashi","year":"2018","journal-title":"Lab Anim Res"},{"issue":"8","key":"pcbi.1012908.ref081","doi-asserted-by":"crossref","first-page":"e0221011","DOI":"10.1371\/journal.pone.0221011","article-title":"Modeling dynamics and alternative treatment strategies in acute promyelocytic leukemia","volume":"14","author":"Jr Yoshinari GH","year":"2019","journal-title":"PLoS One"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012908","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T16:09:01Z","timestamp":1744214941000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012908"}},"subtitle":[],"editor":[{"given":"David Basanta","family":"Gutierrez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,9]]},"references-count":81,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1012908","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.04.23.590738","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,9]]}}}