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CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells.

Authors :
Storci G
De Felice F
Ricci F
Santi S
Messelodi D
Bertuccio SN
Laprovitera N
Dicataldo M
Rossini L
De Matteis S
Casadei B
Vaglio F
Ursi M
Barbato F
Roberto M
Guarino M
Asioli GM
Arpinati M
Cortelli P
Maffini E
Tomassini E
Tassoni M
Cavallo C
Iannotta F
Naddeo M
Tazzari PL
Dan E
Pellegrini C
Guadagnuolo S
Carella M
Sinigaglia B
Pirazzini C
Severi C
Garagnani P
Kwiatkowska KM
Ferracin M
Zinzani PL
Bonafè M
Bonifazi F
Source :
The Journal of clinical investigation [J Clin Invest] 2024 Jun 04; Vol. 134 (14). Date of Electronic Publication: 2024 Jun 04.
Publication Year :
2024

Abstract

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).

Details

Language :
English
ISSN :
1558-8238
Volume :
134
Issue :
14
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
38833312
Full Text :
https://doi.org/10.1172/JCI173096