Extracellular Vesicles as Biomarkers of Neurotoxicity and Cytokine Release Syndrome after anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy

Chimeric Antigen Receptor (CAR) T-cell therapy represents one of the most promising immunotherapies for haematological malignancies. However, it has been associated with life threatening toxicities: cytokine release syndrome (CRS) and neurotoxicity (ICANS). Endothelial dysfunction and T-cell activation are involved in both toxicities making extracellular vesicles (EVs) a potential attractive biomarker. In this study we investigated the immunophenotype of different EVs subsets (total and CD146/CD144+ exosomes and microvescicles) in the plasma of a cohort of 27 CAR T-cell recipients and we analysed their potential correlation with the toxicities by Logistic Regression Analysis and Cox Proportional-Hazards Models. The correlation was analysed in two different timeframes, before the treatment and before the onset of the toxicities. The aim is to early identify patients at higher risk of developing CRS and ICANS after the CAR T-cell therapy and in future to make clinical interventions accordingly. Onset of CRS was associated with CD8, CD69 and CD63 in total exosomes, whereas onset of ICANS was associated with CD2 in total microvesicles, HLA-DpDqDr in CD146/CD144+ exosomes and SSEA4 in CD146/CD144+ microvesicles. In addition, we observed that some biomarker changes were also detectable several days before the treatment. To confirm and validate our findings a larger prospective study will start in the next future.