Th1/Th17 轴调控嵌合抗原受体（CAR）T 细胞治疗毒性

CAR-T therapy has led to significant improvements in patient survival.

However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematologic toxicity (ICAHT).

We utilized IL-2R knockout mice to model cytokine toxicities with elevated levels of IL6, IFN , and TNF and increased M1-like macrophages. Onset of CRS was accompanied by a reduction in peripheral blood neutrophils due to disruption of bone marrow neutrophil homeostasis characterized by an increase in apoptotic neutrophils and a decrease in proliferative and mature neutrophils.

Both non-tumor-bearing and E -ALL tumor-bearing mice recapitulated the co-occurrence of CRS and neutropenia. IFN -blockade alleviated CRS and neutropenia without affecting CAR-T efficacy.

Mechanistically, a Th1-Th17 imbalance was observed to drive co-occurrence of CRS and neutropenia in an IFN -dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN -to-IL-17A ratio in the peripheral blood during high-grade CRS and neutropenia.

We have uncovered a biological basis for ICAHT and provide support for the use of IFN -blockade to reduce CRS and neutropenia.