 Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignanciesSimona Manni,
Francesca Del Bufalo,
Pietro Merli,
Domenico Alessandro Silvestris,
Marika Guercio,
Simona Caruso,
Sofia Reddel,
Laura Iaffaldano,
Michele Pezzella,
Stefano Di Cecca,
Matilde Sinibaldi,
Alessio Ottaviani,
Maria Cecilia Quadraccia,
Mariasole Aurigemma,
Andrea Sarcinelli,
Roselia Ciccone,
Zeinab Abbaszadeh,
Manuela Ceccarelli,
Rita De Vito,
Maria Chiara Lodi,
Maria Giuseppina Cefalo,
Angela Mastronuzzi,
Biagio De Angelis (),
Franco Locatelli () and
Concetta Quintarelli
Nature Communications, 2023, vol. 14, issue 1, 1-13 Abstract: Abstract Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans. Date: 2023 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38723-y Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-023-38723-y Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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