eprintid: 10204319
rev_number: 7
eprint_status: archive
userid: 699
dir: disk0/10/20/43/19
datestamp: 2025-02-05 11:19:27
lastmod: 2025-02-05 11:19:27
status_changed: 2025-02-05 11:19:27
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Bove, Camilla
creators_name: Arcangeli, Silvia
creators_name: Falcone, Laura
creators_name: Camisa, Barbara
creators_name: El Khoury, Rita
creators_name: Greco, Beatrice
creators_name: De Lucia, Anna
creators_name: Bergamini, Alice
creators_name: Bondanza, Attilio
creators_name: Ciceri, Fabio
creators_name: Bonini, Chiara
creators_name: Casucci, Monica
title: CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D19
divisions: G98
note: This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
abstract: Background

To date, T cells redirected with CD19-specific chimeric antigen receptors (CAR) have gained impressive success in B-cell malignancies. However, treatment failures are common and the occurrence of severe toxicities, such as cytokine release syndrome (CRS), still limits the full exploitation of this approach. Therefore, the development of cell products with improved therapeutic indexes is highly demanded.

Methods

In this project, we investigated how CD4 and CD8 populations cooperate during CD19 CAR-T cell responses and what is their specific role in CRS development. To this aim, we took advantage of immunodeficient mice reconstituted with a human immune system (HuSGM3) and engrafted with the B-cell acute lymphoblastic leukemia cell line NALM-6, a model that allows to thoroughly study efficacy and toxicity profiles of CD19 CAR-T cell products.

Results

CD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of adverse events. Accordingly, toxicity assessment in HuSGM3 mice identified CD4 CAR-T cells as key contributors to CRS development, revealing a safer profile when they harbor CARs embedded with 4-1BB, rather than CD28. By comparing differentially co-stimulated CD4:CD8 1:1 CAR-T cell formulations, we observed that CD4 cells shape the overall expansion kinetics of the infused product and are crucial for maintaining long-term responses. Interestingly, the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity, without impacting antitumor efficacy.

Conclusions

Taken together, these data point out that the rational design of improved adoptive T-cell therapies should consider the biological features of CD4 CAR-T cells, which emerged as crucial for maintaining long-term responses but also endowed by a higher toxic potential.
date: 2023-01
date_type: published
publisher: BMJ
official_url: https://doi.org/10.1136/jitc-2022-005878
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2358036
doi: 10.1136/jitc-2022-005878
lyricists_name: Bove, Camilla
lyricists_id: CBOVE38
actors_name: Bove, Camilla
actors_id: CBOVE38
actors_role: owner
full_text_status: public
publication: Journal for ImmunoTherapy of Cancer
volume: 11
number: 1
article_number: e005878
issn: 2051-1426
citation:        Bove, Camilla;    Arcangeli, Silvia;    Falcone, Laura;    Camisa, Barbara;    El Khoury, Rita;    Greco, Beatrice;    De Lucia, Anna;                     ... Casucci, Monica; + view all <#>        Bove, Camilla;  Arcangeli, Silvia;  Falcone, Laura;  Camisa, Barbara;  El Khoury, Rita;  Greco, Beatrice;  De Lucia, Anna;  Bergamini, Alice;  Bondanza, Attilio;  Ciceri, Fabio;  Bonini, Chiara;  Casucci, Monica;   - view fewer <#>    (2023)    CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses.                   Journal for ImmunoTherapy of Cancer , 11  (1)    , Article e005878.  10.1136/jitc-2022-005878 <https://doi.org/10.1136/jitc-2022-005878>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10204319/1/2023%2C%20Bove%20C%20at%20al%2C%20JITC.pdf