Pulmonary safety assessment of cancer immunotherapy on a patient-derived lung-on-chip

Preclinical in vitro and animal models used for assessment of drug safety often fail to predict complications in humans, especially when the drug in question targets the immune system such as in cancer immunotherapy. Adverse events can occur in the lungs, where drugs such as the first approved immunotherapy Interleukin-2 (IL2, Proleukin®) have led to unwanted side effects. In fact, approx. 1/3 of the patients under IL2 therapy develop vascular leak syndrome (VLS), characterized by lung edema, immune cells infiltration and inflammation. To recapitulate this condition, we engineered a breathing chip model of the alveolar-capillary barrier, using patient-derived primary alveolar epithelial cells (AXhAEpC) from several donors in coculture with endothelial cells and peripheral blood mononuclear cells (PBMC). IL2 treatment caused the main hallmarks of pulmonary VLS, only in a portion of tested donors: barrier impairment (TER, permeability) and cytokines upregulation (Luminex Immunoassay). Immune cells harvested from the chips resulted activated and differentiated upon treatment (flow cytometry). Moreover, baseline levels of cytokines were analysed to find potential safety biomarkers candidates for prediction of risk to develop IL2-associated VLS, and/or to better understand the mechanism behind this pathological state. These results highlight the predictive potential of the AXLung-on-chip technology, which reliably reconstructed the healthy alveolus, its impairment upon IL2 treatment, and most importantly, patient-to-patient variability observed in the clinics. This model could therefore contribute advancing cancer immunotherapy drug development, towards medications with a better benefit/risk ratio.