1. extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells
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Storci, Gianluca, De Felice, Francesco, Ricci, Francesca, Santi, Spartaco, Messelodi, Daria, Bertuccio, Salvatore Nicola, Laprovitera, Noemi, Dicataldo, Michele, Rossini, Lucrezia, De Matteis, Serena, Casadei, Beatrice, Vaglio, Francesco, and Ursi, Margherita
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Non-Hodgkin's lymphomas -- Care and treatment -- Prognosis ,Cell organelles -- Health aspects -- Measurement ,Neurotoxicity syndromes -- Risk factors ,Biological markers -- Measurement ,Health care industry - Abstract
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.sup.+] extracellular vesicle ([CAR.sup.+]EV) release was assessed in human CD19.CAR T cells cocultured with [CD19.sup.+] 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.sup.+]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.sup.+]EV-induced neurotoxicity. RESULTS. In vitro release of [CAR.sup.+]EVs occurs within 1 hour after target engagement. Plasma [CAR.sup.+]EVs are detectable 1 hour after infusion. A concentration greater than 132.8 [CAR.sup.+]EVs/[micro]L at hour +1 or greater than 224.5 [CAR.sup.+]EVs/[micro]L at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. [ENO2.sup.+] nanoparticles were released by iPSC-derived neural cells upon [CAR.sup.+]EV exposure and were increased in plasma of patients with ICANS. CONCLUSION. Plasma [CAR.sup.+]EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis. TRIAL REGISTRATION. NCT04892433, NCT05807789. FUNDING. Life 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)., Introduction Anti-CD19 chimeric antigen receptor T (CD19.CAR T) cell therapy changed the treatment of B cell malignancies (1). So far, three CD19.CAR T cell products have received approval from regulatory [...]
- Published
- 2024
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