Neutralizing IFNγ Improves Safety without Compromising Efficacy of CAR-T Cell Therapy in B-cell Malignancies

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 multiorgan 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⁺ lymphomas. 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.

Simona Manni, Francesca Del Bufalo, Pietro Merl, Domenico Alessandro Silvestri, Marika Guercio, Simona Caruso, Sofia Reddel, Laura Iaffaldano, Michele Pezzella, Stefano Di Cecca, Matilde Sinibaldi, Alessio Ottaviani, Maria Cecilia Quadricaccia, Marisaol 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, Concetta Quintarelli