Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults
Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults
复制标题
纳武单抗治疗成人复发/难治性 Epstein-Barr 病毒相关噬血细胞性淋巴组织细胞增多症。
DOI：
10.1182/blood.2019003886
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发表时间：
2020-03-12
期刊：
影响因子：
20.3
通讯作者：
Liu, Ting
中科院分区：
文献类型：
--
作者：
Liu, Pengpeng;Pan, Xiangyu;Liu, Ting
eb病毒（EBV）相关的噬血细胞淋巴组织细胞增多症（EBV- hlh）是一种由EBV感染引发的危及生命的高炎症综合征。鉴于依托泊苷类治疗方案不能有效清除病毒，它经常复发或难治性（r/r）。EBV-HLH在未进行同种异体造血干细胞移植的成人中总是致命的。在这里，我们对7例在华西医院接受纳武单抗同情用药治疗的r/r EBV-HLH患者进行了回顾性分析。7例患者均耐受治疗，6例有反应。其中5例达到并保持临床完全缓解，中位随访时间为16个月（11.4-18.9个月）。重要的是，4例患者的血浆和细胞ebv - dna均被完全根除。单细胞rna测序分析显示，HLH综合征与单核/巨噬细胞过度活跃和CD8 T细胞无效活化程序缺陷有关。Nivolumab治疗扩大了程序性死亡蛋白1阳性T细胞，并恢复了CD8 T细胞中hlh相关的脱颗粒和共刺激基因的表达。我们的数据表明，纳武单抗作为一种单一疗法，很可能通过恢复有缺陷的抗ebv反应，为r/r EBV-HLH提供了一种潜在的治愈方法。
Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median followup of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1-positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.