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bioRxiv · 10.1101/2025.11.22.689920

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

Parameswaran, R.·Fritz, C.·Metheny, L.·Wald, D. N.·Caimi, P.
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Abstract

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-{gamma}, 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-{gamma} 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/689920v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@187a0edorg.highwire.dtl.DTLVardef@1566904org.highwire.dtl.DTLVardef@896b5org.highwire.dtl.DTLVardef@1de5db6_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Parameswaran, R., Fritz, C., Metheny, L., Wald, D. N., Caimi, P.. 2025-11-25. B-cell activating factor plays a critical role in CAR-T cell-associated cytokine release syndrome. https://doi.org/10.1101/2025.11.22.689920

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