TY - JOUR
T1 - Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies
AU - Manni, Simona
AU - Del Bufalo, Francesca
AU - Merli, Pietro
AU - Silvestris, Domenico Alessandro
AU - Guercio, Marika
AU - Caruso, Simona
AU - Reddel, Sofia
AU - Iaffaldano, Laura
AU - Pezzella, Michele
AU - Di Cecca, Stefano
AU - Sinibaldi, Matilde
AU - Ottaviani, Alessio
AU - Quadraccia, Maria Cecilia
AU - Aurigemma, Mariasole
AU - Sarcinelli, Andrea
AU - Ciccone, Roselia
AU - Abbaszadeh, Zeinab
AU - Ceccarelli, Manuela
AU - De Vito, Rita
AU - Lodi, Maria Chiara
AU - Cefalo, Maria Giuseppina
AU - Mastronuzzi, Angela
AU - De Angelis, Biagio
AU - Locatelli, Franco
AU - Quintarelli, Concetta
PY - 2023
Y1 - 2023
N2 - 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 IFN gamma 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 IFN gamma 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-IFN gamma 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.
AB - 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 IFN gamma 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 IFN gamma 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-IFN gamma 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.
KW - CAR-T cell therapy
KW - CAR-T cell therapy
UR - http://hdl.handle.net/10807/258554
U2 - 10.1038/s41467-023-38723-y
DO - 10.1038/s41467-023-38723-y
M3 - Article
SN - 2041-1723
VL - 14
SP - 1
EP - 13
JO - Nature Communications
JF - Nature Communications
ER -