阻断或缺失 IFNγ 降低巨噬细胞活化且不损害血液系统恶性肿瘤中 CAR-T 细胞功能

UNLABELLED: Chimeric antigen receptor (CAR) T cells induce impressive responses in patients with hematologic malignancies but can also trigger cytokine release syndrome (CRS), a systemic toxicity caused by activated CAR T cells and innate immune cells. Although IFN 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 IFN reduced immune checkpoint protein expression with no detrimental effect on antitumor efficacy against hematologic malignancies in vitro or in vivo.

Furthermore, IFN blockade reduced macrophage activation to a greater extent than currently used cytokine antagonists in immune cells from healthy donors and serum from patients with CAR T-cell-treated lymphoma who developed CRS. Collectively, these data show that IFN is not required for CAR T-cell efficacy against hematologic malignancies, and blocking IFN could simultaneously mitigate cytokine-related toxicities while preserving persistence and antitumor efficacy.

SIGNIFICANCE: Blocking IFN in CAR T cells does not impair their cytotoxicity against hematologic tumor cells and paradoxically enhances their proliferation and reduces macrophage-mediated cytokines and chemokines associated with CRS.

These findings suggest that IFN blockade may improve CAR T-cell function while reducing treatment-related toxicity in hematologic malignancies. See related content by McNerney et al. , p. 90 (17). This article is highlighted in the In This Issue feature, p. 85.