Modeling the mechanisms of CAR-T–associated CRS and neutropenia

Goala P, Zhang Y, Beatty NJ, et al. IFNγ-Driven Skewing Towards Th1 Over Th17 Differentiation Underlies CRS and Neutropenia in CAR-T Therapy. Journal of Clinical Investigation. 2025; (doi: 10.1172/JCI194631).

IFNγ blockade curtails the incidence of high-grade toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, researchers report. Observations from a murine model of toxicities with high levels of IL6, IFNγ, and TNFα provided insight into the drivers of cytokine release syndrome (CRS) and neutropenia in the setting of CAR T-cell immunotherapy. In IL-2Rα knockout mice exposed to CAR T therapy, the presence of IFNγ favored Th1 over Th17, leading to CRS and neutropenia—even in the absence of tumors. However, when IFNγ was blocked, the toxicities did not present in the lab subjects. Importantly, the study authors note that IFNγ blockade quieted CRS and neutropenia without reducing CAR-T efficacy.

Read More