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

Alexander Mazein^1*Oxana Lopata¹Kristin Reiche^2,3,4Katherina Sewald⁵Miriam Alb⁶Christina Sakellariou⁷Patricia Gogesch⁸Hannah Morgan⁹Vanessa Neuhaus^10,11Nhu-Nguyen Pham^12,2Charline Sommer^10,11Ethan Perkins^13,14Birgit Fogal¹⁵Muhammad Shoaib¹Reinhard Schneider^1,16Venkata P. Satagopam^1,16Marek Ostaszewski^1,16*

• ¹Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue du Swing, L-4367, Belvaux, Luxembourg
• ²Fraunhofer Institute for Cell Therapy and Immunology IZI, Department of Diagnostics, Perlickstraße 1, 04103, Leipzig, Germany
• ³Institute for Clinical Immunology, University Hospital Leipzig, Leipzig, Lower Saxony, Germany
• ⁴Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Leipzig, Germany
• ⁵Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625, Hannover, Germany
• ⁶Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Lehrstuhl für Zelluläre Immuntherapie, Versbacher Straße 5, 97078, Würzburg, Germany
• ⁷Lund University, Department of Immunotechnology, 223 81, Lund, Sweden
• ⁸Paul-Ehrlich-Institut, Division of Immunology, Paul-Ehrlich-Str. 51-59, 63225, Langen, Germany
• ⁹Novartis Biomedical Research, Preclinical Safety, CH-4056, Basel, Switzerland
• ¹⁰Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Preclinical Pharmacology and In-Vitro Toxicology, Nikolai-Fuchs-Str. 1, 30625, Hannover, Germany
• ¹¹Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL) and CIMD, Hannover, Germany
• ¹²Fraunhofer Institute for Cell Therapy and Immunology IZI, Department of Vaccines and Infection Models, Perlickstraße 1, 04103, Leipzig, Germany
• ¹³LabCorp Drug Development, Harrogate, England, United Kingdom
• ¹⁴Institute of Cancer Therapeutics, Faculty of Life Sciences, School of Pharmacy and Medical Sciences, University of Bradford, Bradford, United Kingdom
• ¹⁵Boehringer Ingelheim Pharmaceuticals Inc., Nonclinical Drug Safety, Ridgefield, Connecticut, United States
• ¹⁶ELIXIR Luxembourg, 6 Avenue du Swing, L-4367, Belvaux, Luxembourg

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. 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. 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.