Article
作者: Cavallo, Carola ; Asioli, Gian Maria ; Garagnani, Paolo ; Ricci, Francesca ; Zinzani, Pier Luigi ; Kwiatkowska, Katarzyna Malgorzata ; Maffini, Enrico ; Bonifazi, Francesca ; Pirazzini, Chiara ; Casadei, Beatrice ; Messelodi, Daria ; Dan, Elisa ; Iannotta, Francesco ; Sinigaglia, Barbara ; Vaglio, Francesca ; Bonafè, Massimiliano ; Arpinati, Mario ; Laprovitera, Noemi ; Ferracin, Manuela ; De Felice, Francesco ; Ursi, Margherita ; Naddeo, Maria ; Bertuccio, Salvatore Nicola ; Carella, Matteo ; Barbato, Francesco ; Storci, Gianluca ; Tazzari, Pier Luigi ; Cortelli, Pietro ; Tomassini, Enrica ; De Matteis, Serena ; Tassoni, Marta ; Guarino, Maria ; Rossini, Lucrezia ; Pellegrini, Cinzia ; Severi, Caterina ; Guadagnuolo, Serafina ; Santi, Spartaco ; Dicataldo, Michele ; Roberto, Marcello
BACKGROUNDPredicting 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.METHODSCAR+ 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.RESULTSIn 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/μL at hour +1 or greater than 224.5 CAR+EVs/μL 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.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).