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

被引：2

作者：

Storci, Gianluca ^{[1
]}

De Felice, Francesco ^{[1
,2
]}

Ricci, Francesca ^{[1
]}

Santi, Spartaco ^{[3
,4
]}

Messelodi, Daria ^{[1
]}

Bertuccio, Salvatore Nicola ^{[1
]}

Laprovitera, Noemi ^{[1
]}

Dicataldo, Michele ^{[1
,2
]}

Rossini, Lucrezia ^{[2
]}

De Matteis, Serena ^{[1
]}

Casadei, Beatrice ^{[1
]}

Vaglio, Francesca ^{[1
]}

Ursi, Margherita ^{[1
,2
]}

Barbato, Francesco ^{[1
,2
]}

Roberto, Marcello ^{[1
,2
]}

Guarino, Maria ^{[1
]}

Asioli, Gian Maria ^{[1
]}

Arpinati, Mario ^{[1
]}

Cortelli, Pietro ^{[5
,6
]}

Maffini, Enrico ^{[1
]}

Tomassini, Enrica ^{[1
]}

Tassoni, Marta ^{[2
]}

Cavallo, Carola ^{[7
]}

Iannotta, Francesco ^{[1
]}

Naddeo, Maria ^{[1
,2
]}

Tazzari, Pier Luigi ^{[1
]}

Dan, Elisa ^{[1
]}

Pellegrini, Cinzia ^{[1
]}

Guadagnuolo, Serafina ^{[1
]}

Carella, Matteo ^{[1
,2
]}

Sinigaglia, Barbara ^{[1
]}

Pirazzini, Chiara ^{[2
]}

Severi, Caterina ^{[8
]}

Garagnani, Paolo ^{[1
,2
]}

Kwiatkowska, Katarzyna Malgorzata ^{[2
]}

Ferracin, Manuela ^{[1
,2
]}

Zinzani, Pier Luigi ^{[2
,9
]}

Bonafe, Massimiliano ^{[1
,2
]}

Bonifazi, Francesca ^{[1
]}

机构：

[1] IRCCS, Azienda Osped Univ Bologna, Bologna, Italy

[2] Univ Bologna, Dipartimento Sci Med & Chirurg, Bologna, Italy

[3] IRCCS, Ist Ortoped Rizzoli, Bologna, Italy

[4] Natl Res Council Italy, Inst Mol Genet, Bologna, Italy

[5] Univ Bologna, Bellaria Hosp, Dept Biomed & Neuromotor Sci, Bologna, Italy

[6] IRCCS, Bellaria Hosp, Inst Neurol Sci Bologna, Bologna, Italy

[7] IRCCS, Res & Innovat Technol Dept, Ist Ortoped Rizzoli, Lab Ramses, Bologna, Italy

[8] Abbelight, Cachan, France

[9] IRCCS, Azienda Osped Univ Bologna, Ist Ematol Seragnoli, Bologna, Italy

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2024年 / 134卷 / 14期

关键词：

THERAPY; NEUROTOXICITY; MANAGEMENT; CHILDREN; ADULTS; BLOOD;

D O I：

10.1172/JCI173096

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：17

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