A Computational Model of Cytokine Release Syndrome during CAR T‐Cell Therapy

Zhang, Zhuoyu; Liu, J.; Ma, Caihong; Chen, Weiqiang

doi:10.1002/adtp.202200130

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…Developing this platform could expand in silico methods in synthetic immunotherapy and create a pipeline similar to how GJSM is currently used to test circuit designs for synthetic development 33 . While computational efforts for synthetic immunotherapy begin with this study, similar efforts are at least underway for regular CAR T cell immunotherapy [58][59][60][61][62] .…”

Section: Discussionmentioning

confidence: 99%

Design and Mathematical Analysis of Activating Amplifiers that Enable Modular Temporal Control in Synthetic Circuits

Lam

2023

Preprint

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The ability to control mammalian cells such that they self-organize or enact therapeutic effects as desired has incredible implications. Not only would it further our understanding of native processes such as development and the immune response, but it would also have powerful applications in medical fields such as regenerative medicine and immunotherapy. This control is typically obtained by synthetic circuits that use synthetic receptors, but control remains incomplete. For example, the synthetic juxtacrine receptors (SJRs) are widely used as they are fully modular and enable spatial control, but they have limited gene expression amplification and temporal control. I therefore designed transcription factor based amplifiers that amplify gene expression and enable unidirectional temporal control by prolonging duration of target gene expression. Using an in silico framework for SJR signaling, I combined these amplifiers with SJRs and show that these SJR amplifier circuits can improve the quality of self-organization and direct different spatiotemporal patterning. I then show that these circuits can improve chimeric antigen receptor (CAR) T cell tumor killing against two different types of tumors. These amplifiers are flexible tools that improve control over SJR based circuits and have both basic and therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Design and Mathematical Analysis of Activating Amplifiers that Enable Modular Temporal Control in Synthetic Circuits

Lam

2023

Preprint

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“…CRS can also be examined through determining the rate of production of key cytokines post therapy administration (either by CAR T cells or other sources in the body). Models can help predict the dynamics of cytokine release to direct timing of intervention measures and offer methods to demonstrate the interaction between prophylactic drugs and CAR T cells ( Hardiansyah and Ng, 2019 ; Stein et al, 2019 ; Zhang Z. et al, 2022 ). These models in conjunction with secretory profiling methods discussed in previous sections may provide additional depletion strategies to avoid CRS.…”

Section: In Silico Approaches To Investigate Car T-cell Function and ...mentioning

confidence: 99%

Current advances in experimental and computational approaches to enhance CAR T cell manufacturing protocols and improve clinical efficacy

Colina,

Shah,

Shah

et al. 2024

Front. Mol. Med

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Since the FDA’s approval of chimeric antigen receptor (CAR) T cells in 2017, significant improvements have been made in the design of chimeric antigen receptor constructs and in the manufacturing of CAR T cell therapies resulting in increased in vivo CAR T cell persistence and improved clinical outcome in certain hematological malignancies. Despite the remarkable clinical response seen in some patients, challenges remain in achieving durable long-term tumor-free survival, reducing therapy associated malignancies and toxicities, and expanding on the types of cancers that can be treated with this therapeutic modality. Careful analysis of the biological factors demarcating efficacious from suboptimal CAR T cell responses will be of paramount importance to address these shortcomings. With the ever-expanding toolbox of experimental approaches, single-cell technologies, and computational resources, there is renowned interest in discovering new ways to streamline the development and validation of new CAR T cell products. Better and more accurate prognostic and predictive models can be developed to help guide and inform clinical decision making by incorporating these approaches into translational and clinical workflows. In this review, we provide a brief overview of recent advancements in CAR T cell manufacturing and describe the strategies used to selectively expand specific phenotypic subsets. Additionally, we review experimental approaches to assess CAR T cell functionality and summarize current in silico methods which have the potential to improve CAR T cell manufacturing and predict clinical outcomes.

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“…Different aspects of CAR-T cell therapy were investigated by modeling approaches [17, 18, 19, 20] with a few focusing on CRS [21, 22, 23, 24]. However, the critical role of macrophages on cytokine release was rarely addressed [25]. It is currently unclear how the different macrophage-associated mechanisms influences the extent and the temporal dynamics of CRS, although these aspects are essential for clinical implementation of countermeasures.…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome

Santurio,

Barros,

Glauche

et al. 2024

Preprint

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Chimeric antigen receptor (CAR)-T cell therapy holds significant potential for cancer treatment, although disease recurrence and cytokine release syndrome (CRS) remain as frequent clinical challenges. To better understand the underlying mechanisms and temporal dynamics during CAR-T cell therapy response we developed a novel multi-layer mathematical model that accurately describes 25 patient time-courses with diverse responses and IL-6 cytokine kinetics. We successfully link the dynamic shape of the response to interpretable model parameters and study the influence of CAR-T cell dose and initial tumor burden on CRS occurrence and treatment outcome. Further accounting for three established mechanisms 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. Our study underscores the utility of mechanistic modeling in deciphering therapy dynamics and guiding clinical interventions, emphasizing the importance of close integration with clinical data.

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A Computational Model of Cytokine Release Syndrome during CAR T‐Cell Therapy

Cited by 3 publications

References 53 publications

Design and Mathematical Analysis of Activating Amplifiers that Enable Modular Temporal Control in Synthetic Circuits

Design and Mathematical Analysis of Activating Amplifiers that Enable Modular Temporal Control in Synthetic Circuits

Current advances in experimental and computational approaches to enhance CAR T cell manufacturing protocols and improve clinical efficacy

Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome

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