CAR+ Extracellular Vesicles Predict ICANS in Patients with B Cell Lymphomas Treated with CD19-directed CAR T Cells.

BACKGROUND. Predicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking. METHODS. CAR + extracellular vesicle (CAR + EV) release was assessed in human CD19.CAR T cells cocultured with CD19 + target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR + EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell- derived (iPSC-derived) neural cells were used as a model for CAR + EV-induced neurotoxicity. RESULTS. In vitro release of CAR + EVs occurs within 1 hour after target engagement. Plasma CAR + EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR + EVs/ mu L at hour +1 or greater than 224.5 CAR + EVs/ mu L at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2 + nanoparticles were released by iPSC-derived neural cells upon CAR + EV exposure and were increased in plasma of patients with ICANS. CONCLUSION. Plasma CAR + EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.