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

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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 ⁺ 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/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.

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.

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).

Abstract

The release of CAR ⁺extracellular vesicles by CD19.CAR T cells upon target engagement is a reliable in vivo predictor of immune effector cell–associated neurotoxicity syndrome.

Related collections

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Author and article information

Contributors

Gianluca Storci

Francesco De Felice

Francesca Ricci

Spartaco Santi:

ORCID: https://orcid.org/0000-0001-9856-7053

Daria Messelodi

Salvatore Nicola Bertuccio

Noemi Laprovitera

Michele Dicataldo

Lucrezia Rossini

Serena De Matteis

Beatrice Casadei

Francesca Vaglio

Margherita Ursi

Francesco Barbato

Marcello Roberto

Maria Guarino

Gian Maria Asioli

Mario Arpinati

Pietro Cortelli

Enrico Maffini

Enrica Tomassini

Marta Tassoni

Carola Cavallo

Francesco Iannotta

Maria Naddeo

Pier Luigi Tazzari

Elisa Dan

Cinzia Pellegrini

Serafina Guadagnuolo

Matteo Carella

Barbara Sinigaglia

Chiara Pirazzini

Caterina Severi

Paolo Garagnani

Katarzyna Malgorzata Kwiatkowska:

ORCID: https://orcid.org/0000-0002-1536-5024

Manuela Ferracin

Pier Luigi Zinzani

Massimiliano Bonafè

Francesca Bonifazi

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J Clin Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date (Electronic, pub): 4 June 2024

Publication date (Electronic, collection): 15 July 2024

Publication date PMC-release: 4 June 2024

Volume: 134

Issue: 14

Electronic Location Identifier: e173096

Affiliations

[1 ]IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

[2 ]Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.

[3 ]IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

[4 ]Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy.

[5 ]Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, Università di Bologna, Bologna, Italy.

[6 ]IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.

[7 ]Laboratory Ramses, Research & Innovation Technology Department, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

[8 ]Abbelight, Cachan, France.

[9 ]IRCCS Azienda Ospedaliero–Università di Bologna, Istituto di Ematologia “Seràgnoli,” Bologna, Italy.

Author notes

Address correspondence to: Massimiliano Bonafè, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Università di Bologna, Via San Giacomo 14, 40134 Bologna, Italy. Phone: 39.51.2094748; Email: massimiliano.bonafe@ 123456unibo.it .

Authorship note: GS and FDF contributed equally to this work and are co–first authors. MB and F Bonifazi contributed equally to this work and are co–senior authors.

Author information

Spartaco Santi https://orcid.org/0000-0001-9856-7053

Katarzyna Malgorzata Kwiatkowska https://orcid.org/0000-0002-1536-5024

Article

Publisher ID: 173096

DOI: 10.1172/JCI173096

PMC ID: 11245152

PubMed ID: 38833312

SO-VID: cc04de99-828a-40b7-b215-af581f2e5422

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 16 June 2023

Date accepted : 24 May 2024

Funding

Funded by: NEXTGENERATION EU (NGEU)

Award ID: project MNESYS (PE0000006)

Funded by: Italian Health ministry

Award ID: ”Life Science Hub - Advanced Therapies (LSH - AT) Financed by Health Ministry as a part of the The National Plan for Complementary Investments to the NRRP - E.3 Innovative health eco system for APC fees

Award ID: immunomonitoring

Funded by: Italian Ministry of University and reaserch

Award ID: HEAL ITALIA- Health Extended ALliance for Innovative Therapies,Advanced Lab-research,

Award ID: Integrated Approaches of Precision Medicine - funding from MUR under the National Recovery

Award ID: Resilience Plan (NRRP),Mission 4 Component 2 Investment 1.3 funded f