ArticlePLoS computational biology2025
Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome.
Article in PLoS computational biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Patient-Specific Determinants of Response to BCMA- and GPRC5D-Targeted CAR T-Cell Therapy in Multiple Myeloma: A QSP Analysis of Clinical Trial and Real-World Data.Clinical pharmacology and therapeutics · 2026Article
- MISSTE: a multiscale integrative spatial simulator for understanding the mechanisms underlying tissue ecosystems.bioRxiv : the preprint server for biology · 2026Article
- Re-evaluating cytokine storm syndromes: dysregulated host defense or contextual immune adaptation?European cytokine network · 2026Review
- Beyond the infusion: nursing at the vanguard of cytokine release syndrome rescue in CAR-T cell therapy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Anti-CD19 CAR T-cell therapy for autoimmune diseases: from exploratory clinical trials to quantitative pharmacodynamic modeling development.Frontiers in immunology · 2026Review
- Challenges and strategies in clinical applications of CAR-T therapy for autoimmune diseases.Journal of hematology & oncology · 2025Review
- Practical Pharmacokinetic-Pharmacodynamic Models in Oncology.Pharmaceutics · 2025Review
- Predicting treatment-free remission in chronic myeloid leukemia patients using an integrated model of tumor-immune dynamics.NPJ systems biology and applications · 2025Article
- Analysing the Structural Identifiability and Observability of Mechanistic Models of Tumour Growth.Bioengineering (Basel, Switzerland) · 2025Article
- Lymphoid and Myeloid Proliferations After Chimeric Antigen Receptor (CAR) T-Cell Therapy: The Pathologist's Perspective.International journal of molecular sciences · 2025Review
- Cytokine release syndrome and CAR T Cell therapy: Modulating the intensity of the inflammatory response and resolution within the tumor microenvironment.Frontiers in pharmacology · 2025Review
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
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.
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Registered trials
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