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Perspective of using in vitro models to understand immunotherapy-induced cytokine release syndrome

Ethan Perkins1,2, Christopher Cooper2, Emma Lund2

  • 1Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom.

Frontiers in Immunology
|January 26, 2026
PubMed

Insights

New in vitro models, like advanced cytokine release assays (CRAs), are crucial for predicting immune-related adverse events. These methods improve drug safety testing and clinical management of toxicities such as cytokine release syndrome (CRS).

Area of Science:

  • Immunotoxicology
  • Drug Development
  • In Vitro Toxicology

Background:

  • The TGN1412 trial failure highlighted limitations in predicting cytokine release syndrome (CRS) using preclinical models.
  • The IMI2/EU immune safety avatar (imSAVAR) consortium was formed to develop tools for assessing immunomodulatory therapy safety.
  • Adverse Outcome Pathway (AOP) concepts are utilized to understand and predict immune-related adverse effects.

Purpose of the Study:

  • To review recent advancements in in vitro cytokine release assay (CRA) models.
  • To discuss the impact of these advanced CRA models on nonclinical toxicology and understanding immune-related adverse outcomes.
  • To provide guidance on selecting appropriate in vitro CRA models for safety assessment.

Main Methods:

  • Review of recent developments in advanced in vitro CRA models.
  • Analysis of the application of New Approach Methodologies (NAMs) in immunological safety testing.
  • Exploration of the Adverse Outcome Pathway (AOP) framework for immune-related adverse effects.

Main Results:

  • Advanced in vitro CRA models are rapidly evolving, offering enhanced predictive capabilities for immunological safety.
  • These models are crucial for hazard identification and improving the prediction of adverse outcomes like CRS.
  • The integration of NAMs and AOPs is transforming immunotoxicology and nonclinical safety assessment.

Conclusions:

  • Advanced in vitro CRA models are essential for improving the prediction of immune-related adverse events in early drug development.
  • These methodologies enhance the understanding and management of toxicities such as CRS.
  • Guidance on model selection is provided to optimize nonclinical toxicology and safety testing.
Keywords:
adverse outcome pathway (AOP)clinical relevancecytokine release syndromeimmunotoxicologymicrophysiological systemorgan on chip

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