학술논문
CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells.
Document Type
Academic Journal
Author
Storci G; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; De Felice F; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Ricci F; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Santi S; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy.; Messelodi D; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Bertuccio SN; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Laprovitera N; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Dicataldo M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Rossini L; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.; De Matteis S; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Casadei B; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Vaglio F; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Ursi M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Barbato F; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Roberto M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Guarino M; IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.; Asioli GM; IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.; Arpinati M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Cortelli P; Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.; Maffini E; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Tomassini E; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Tassoni M; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.; Cavallo C; Laboratory RAMSES, Rizzoli Orthopaedic Institute, Bologna, Italy.; Iannotta F; IRCCS Azienda ospedaliero-Universitaria di Bologna, Bologna, Italy.; Naddeo M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Tazzari PL; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Dan E; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Pellegrini C; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Guadagnuolo S; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Carella M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Sinigaglia B; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Pirazzini C; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.; Severi C; Abbelight, Cachan, France.; Garagnani P; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.; Kwiatkowska KM; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.; Ferracin M; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.; Zinzani PL; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Bonafè M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Bonifazi F; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Source
Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Predicting Immune-effector Cell Associated Neurotoxicity Syndrome (ICANS) in patients infused with Chimeric Antigen Receptor T cells (CAR-T) 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: Human CD19.CAR-T cells were generated to gain insight into CAR+ extracellular vesicle (CAR+EV) release upon target engagement. A prospective cohort of 100 B-cell lymphoma patients infused with approved CD19.CAR-T cell products (axi-cel, brexu-cel and tisa-cel) was assessed for plasma CAR+EVs as potential biomarkers of in vivo CD19.CAR-T cell activation and predictors of ICANS. Human induced pluripotent stem cells (iPSCs)-derived neural cells were used as a model for CAR+EV-induced neurotoxicity.
Results: In vitro, exosome-like CAR+EVs were released by CD19.CAR-T cells upon target engagement. In vivo, CAR+EVs were detectable as early as 1 hour in the plasma of patients. A concentration > 132.8 CAR+EVs/μl at hour +1 or > 224.5 CAR+EVs/μl at day +1 predicted ICANS in advance of 4 days, with a sensitivity up to 96.55% and a specificity up to 80.36%, outperforming other potential ICANS predictors. Enolase 2 (ENO2+) nanoparticles were released by iPSCs-derived neural cells upon CAR+EVs exposure and were increased in the plasma of ICANS patients.
Conclusions: These results convey that 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.
Trial Registration: NCT04892433, NCT05807789.
Methods: Human CD19.CAR-T cells were generated to gain insight into CAR+ extracellular vesicle (CAR+EV) release upon target engagement. A prospective cohort of 100 B-cell lymphoma patients infused with approved CD19.CAR-T cell products (axi-cel, brexu-cel and tisa-cel) was assessed for plasma CAR+EVs as potential biomarkers of in vivo CD19.CAR-T cell activation and predictors of ICANS. Human induced pluripotent stem cells (iPSCs)-derived neural cells were used as a model for CAR+EV-induced neurotoxicity.
Results: In vitro, exosome-like CAR+EVs were released by CD19.CAR-T cells upon target engagement. In vivo, CAR+EVs were detectable as early as 1 hour in the plasma of patients. A concentration > 132.8 CAR+EVs/μl at hour +1 or > 224.5 CAR+EVs/μl at day +1 predicted ICANS in advance of 4 days, with a sensitivity up to 96.55% and a specificity up to 80.36%, outperforming other potential ICANS predictors. Enolase 2 (ENO2+) nanoparticles were released by iPSCs-derived neural cells upon CAR+EVs exposure and were increased in the plasma of ICANS patients.
Conclusions: These results convey that 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.
Trial Registration: NCT04892433, NCT05807789.