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Marvel
(2022-02-28 14:52):
#paper title: Blockade or Deletion of IFNγ Reduces Macrophage Activation without Compromising CAR T-cell Function in Hematologic Malignancies
#link: https://pubmed.ncbi.nlm.nih.gov/35015685/
#doi: 10.1158/2643-3230.BCD-21-0181
导读：CAR-T疗法已在血液瘤患者上产出良好结果，但通常会诱发细胞介导的临床毒性，这不仅仅会损害患者身体健康，同时会加重患者经济负担，因为他们会因此而延长住院时间。目前临床上的细胞因子拮抗剂并不能完全缓解这些副反应，即使是预防性给药也不成，大概是因为这些拮抗剂仅靶向炎症的下游因素。由T细胞介导的细胞因子IFNγ作为CRS的生物标志物之一， 也是固有免疫细胞可能的激活子。基于IFNγ和CRS之间强的临床相关性，本文研究团队将IFNγ通路确定为潜在靶标。这一方法直接靶向CAR-T细胞本身，而不是下游巨噬细胞功能，有可能将临床毒性阻断在发生之前。并基于实验地提出：提出CAR-T有效性和细胞毒性并非唇齿相依，是可以分割开来的，以更好地改善临床效果。
Abstract:
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 …
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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 IFNγ 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 IFNγ reduced immune checkpoint protein expression with no detrimental effect on antitumor efficacy against hematologic malignancies in vitro or in vivo. Furthermore, IFNγ 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 IFNγ is not required for CAR T-cell efficacy against hematologic malignancies, and blocking IFNγ could simultaneously mitigate cytokine-related toxicities while preserving persistence and antitumor efficacy.
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