Mathematical Modeling Unveils the Timeline of CAR-T Cell Therapy and Macrophage-mediated Cytokine Release Syndrome
Daniela S Santurio, Luciana R C Barros, Ingmar Glauche, Artur c Fassoni.
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.
Introduction
Immunotherapy with chimeric antigen receptor T (CAR-T) cells is a groundbreaking approach that harnesses the power of the immune system to fight hematological and non-hematological malignancies. Genetic engineering enables T cells to express chimeric antigen receptors (CARs), enhancing their ability to specifically recognize and eliminate cancer cells. This remarkable efficacy in treating certain types of blood cancers made CAR-T cell therapy a promising avenue in oncology, with new CAR designs entering clinical trials for several indications, including solid tumors.
Materials and Methods:
We did an extensive search in the literature for datasets containing patient time courses with enough data points for fitting multiphasic CAR-T kinetics and IL 6 kinetics. We then included in our modeling all datasets satisfying these requirements. Individual pharmacokinetic profiles of patients undergoing anti-CD19 CAR-T cell therapy were digitized from and we collected the raw data disclosed in. A detection limit was set for CAR-T at 25 copies/μg DNA or 2.5x10 cells (for conversions see Model Setup) and relapse was defined as the absolute number of total tumor cells exceeding its initial tumor burden.
Discussion
We developed a novel multi-layer mathematical model to investigate tumor response and CRS following CAR-T cell immunotherapy. The model accurately describes the timeline of therapy response and relates its dynamic shape to interpretable model parameters. Our findings highlight the role of early macrophage activation in cytokine release, thereby outlining potential strategies for clinical monitoring and prevention of CRS. By disentangling different modes of macrophage activation we identified the CD40-CD40L axis as a clinically feasible target to control the activation process and modulate IL-6 peak height.
Citation: Santurio DS, Barros LRC, Glauche I, Fassoni Ac (2025) Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome. PLoS Comput Biol 21(4): e1012908. https://doi.org/10.1371/journal.pcbi.1012908
Editor: David Basanta Gutierrez
Received: September 2, 2024; Accepted: February 24, 2025; Published: April 9, 2025.
Copyright: © 2025 Santurio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The patient data that support the findings of this study were collected from existing literature [1,32,56–58]. These data and all author-generated code supporting the results of this study are available on Zenodo at link doi: 10.5281/zenodo.14501736.
Funding: ACF was supported by Alexander von Humboldt Foundation and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
