B-cell activating factor plays a critical role in CAR-T cell-associated cytokine release syndrome.

Cytokine release syndrome (CRS) is the most common and potentially life-threatening toxicity associated with CAR-T cell therapy and is related to a heightened immune effector state. In this work, we identified a novel role of the pro-tumorigenic cytokine B-cell activating factor (BAFF) in its pathophysiology. First, we observed that patients who experienced CAR-T cell-related CRS have elevated serum BAFF levels that coincide with elevated IL-6. Mechanistically, we show that IFN-γ, produced by activated CAR-T cells, stimulates monocytes to release BAFF, which induces the expression of CRS-related cytokines from monocytes. Monocytes derived from CRS patients express BCMA, which is further induced by IFN-γ stimulation. Neutralization of BAFF with belimumab significantly reduces production of various CRS and ICANS-related cytokines without impairing CAR-T cell activation or killing. Overall, we demonstrate that BAFF plays a critical role in CAR-T-cell-related CRS, and its neutralization may be a novel strategy for treating both CRS and ICANS.