European Respiratory Journal
Giulia Raggi, Nuria Roldan, Virginie Micallef, Aude Rapet, Lea De Maddalena, Théo Imler, Laurène Froment, Thomas M. Marti, Ralph A. Schmid, Ekaterina Breous-Nystrom, Adrian B. Roth, Lauriane Cabon, Nina Hobi
Abstract
Systemic administration of Interleukin-2 (IL-2) at high doses in cancer immunotherapy has been associated with vascular leak syndrome (VLS) and pulmonary edema, a life-threatening condition. The complex mechanism of action underlying this medication’s adverse event is not yet well understood, however it has been proposed to result from different events involving cytokine release to the bloodstream and innate immunity: activation of the complement system, neutrophils and endothelial-cell adhesion molecules. The resulting leukocyte infiltration combined with cell death and mechanical stress lead to alveolar-epithelial barrier disruption. We have used advanced microphysiological in vitro model (MPS) to mimic IL-2 – induced VLS in order to recapitulate IL-2 toxicity and test improved molecules for cancer immunotherapy. With that purpose, human epithelial and/or endothelial barrier models were treated with IL-2 in presence of peripheral blood mononuclear cells (PBMC). According to our results, we successfully reproduced IL-2 – induced activation of endothelial cells and PBMCs, indicated by presence of specific biomarkers and cytokines. In our patient derived – alveolar epithelial/endothelial MPS, we could recapitulate VLS main hallmarks upon IL-2 treatment, including barrier disruption (decrease in transbarrier electrical resistance), vascular leakage (increased permeability), cytokine release (e.g. TNFα) and increased cytotoxicity.
The use of patient-derived cells combined with the MPS technology provides a step further towards a personalized approach, where we could identify patients at higher risk of side effects and implement better care solutions.
