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Blockade or deletion of IFNg reduces macrophage activation without compromising CAR-T function in hematologic malignancies.

Chimeric antigen receptor T cells (CAR-T) induce impressive responses in patients with hematologic malignancies but can also trigger cytokine release syndrome (CRS), a systemic toxicity caused by activated CAR-T and innate immune cells. Although interferon-gamma (IFNg) production serves as a potency assay for CAR T cells, its biologic role in conferring responses in hematologic malignancies is not established. Here we show that pharmacologic blockade or genetic knockout of IFNg reduced immune checkpoint protein expression with no detrimental effect on anti-tumor efficacy against hematologic malignancies in vitro or in vivo. Furthermore, IFNg blockade reduced macrophage activation to a greater extent than currently used cytokine antagonists in immune cells from healthy donors and serum from CAR-T treated lymphoma patients who developed CRS. Collectively, these data show that IFNg is not required for CAR-T efficacy against hematologic malignancies, and blocking IFNg could simultaneously mitigate cytokine-related toxicities while preserving persistence and anti-tumor efficacy.