An explorable model of an adverse outcome pathway of cytokine release syndrome related to the administration of immunomodulatory biotherapeutics and cellular therapies.

Introduction: Cytokine release syndrome (CRS) is a potentially severe systemic inflammatory condition triggered by various immunomodulatory therapies, making understanding its pathogenesis critical for improving patient outcomes. Results/Methods: By combining immunotoxicology and systems biology approaches, we offer a novel and integrative conceptual model of CRS as an adverse outcome (AO), induced by five different immunomodulatory biotherapies: 1) chimeric antigen receptor (CAR) T cells, 2) checkpoint inhibitors, 3) T cell engaging bispecific modalities, 4) monoclonal antibodies targeting and activating T cell receptors, and 5) FcγR activating monoclonal antibodies. This model uniquely integrates multiple CRS-inducing therapies into a unified framework, offering a comprehensive mechanistic representation of CRS pathophysiology. For that, we built an adverse outcome pathway (AOP) CRS network for these therapies and then developed a systems biology map of molecular mechanisms relevant to the AOP network. The map of mechanisms is made available via a dedicated online platform for exploration and data visualisation. It includes 24 cell types, 425 entities and 430 interactions. Discussion: Beyond a static representation, the CRS Map serves as a dynamic tool for clinical and research applications, allowing researchers and clinicians to explore CRS progression in detail, identify biomarkers, and discover potential therapeutic targets. The map demonstrates stages of CRS progression and shows molecules that can be measured in relevant immunotoxicological assays, as well as potential drug targets for therapeutic intervention of CRS.