The Th1/Th17 axis regulates chimeric antigen receptor (CAR) T cell therapy toxicities

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{gamma}, 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{gamma}-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{gamma}-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN{gamma}-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{gamma}-blockade to reduce CRS and neutropenia. Statement of SignificanceDespite clinical success of CAR-T therapy, patients develop toxicities such as cytokine release syndrome and neutropenia, whose co-occurrence impacts their survival and quality-of-life. We recapitulate these toxicities in mice to discover their co-occurrence is driven by Th1-Th17 imbalance following CAR-T administration, which can be prevented via IFN{gamma} blockade.