First-line Therapy With Donor-derived Human Cytomegalovirus (HCMV)-specific T Cells Reduces Persistent HCMV Infection by Promoting Antiviral Immunity After Allogenic Stem Cell Transplantation
First-line Therapy With Donor-derived Human Cytomegalovirus (HCMV)-specific T Cells Reduces Persistent HCMV Infection by Promoting Antiviral Immunity After Allogenic Stem Cell Transplantation
复制标题
使用供体来源的人巨细胞病毒 (HCMV) 特异性 T 细胞进行一线治疗，通过在同种异体干细胞移植后促进抗病毒免疫来减少持续性 HCMV 感染。
DOI：
10.1093/cid/ciz368
复制
发表时间：
2020-04-01
影响因子：
11.8
通讯作者：
Huang, Xiao-Jun
中科院分区：
文献类型：
--
作者：
Zhao, Xiang-Yu;Pei, Xu-Ying;Huang, Xiao-Jun
背景。人类巨细胞病毒（HCMV）感染，尤其是持续性HCMV感染，是同种异体干细胞移植（allogenic stem cell transplantation, alloo - sct）术后发病和死亡的重要原因。抗病毒药物仍然是一线治疗，但由于副作用和获得性耐药性的限制。我们评估了供体来源的HCMV特异性细胞毒性T细胞（ctl）作为治疗同种异体细胞移植后HCMV感染的一线疗法的安全性和有效性，并研究了其潜在机制。在人源化HCMV感染小鼠中，一线ctl治疗通过促进体内移植源内源性HCMV特异性免疫的恢复，有效地对抗全身HCMV感染。在一项临床试验中，与配对的高危对照队列相比，一线CTLs治疗显著降低了持续性HCMV感染率（2.9% vs 20.0%, P = 0.018）和晚期HCMV感染率（5.7% vs 20.0%, P = 0.01）和持续性HCMV感染的累积发生率（风险比[HR]， 0.13； 95%可信区间[CI]， 0.10-0.82; P = 0.02），降低了1年治疗相关死亡率（HR, 0.15）。95% ci, 0.11-0.90。P =.03)，提高了1年总生存率（HR, 6.35; 95% CI, 1.05-9.00; P =.04）。此外，一线ctl治疗促进了患者ctl的数量和功能恢复，这与HCMV清除有关。我们为ctl联合抗病毒药物作为治疗HCMV感染的一线疗法的益处提供了强有力的支持，并表明过继性输注ctl可能刺激内源性HCMV特异性免疫的恢复。
Background. Human cytomegalovirus (HCMV) infection, especially persistent HCMV infection, is an important cause of morbidity and mortality after allogenic stem cell transplantation (allo-SCT). Antiviral agents remain the first-line therapy but are limited by side effects and acquired resistance.Methods. We evaluated the safety and efficacy of donor-derived HCMV-specific cytotoxic T cells (CTLs) as a first-line therapy for HCMV infection after allo-SCT and investigated the underlying mechanisms.Results. In humanized HCMV-infected mice, first-line therapy with CTLs effectively combated systemic HCMV infection by promoting the restoration of graft-derived endogenous HCMV-specific immunity in vivo. In a clinical trial, compared with the pairmatched, high-risk control cohort, first-line therapy with CTLs significantly reduced the rate of persistent (2.9% vs 20.0%, P =.018) and late (5.7% vs 20.0%, P =.01) HCMV infection and cumulative incidence of persistent HCMV infection (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.10-0.82; P =.02), lowered 1-year treatment-related mortality (HR, 0.15. 95% CI, 0.11-0.90. P =.03), and improved 1-year overall survival (HR, 6.35; 95% CI, 1.05-9.00; P =.04). Moreover, first-line therapy with CTLs promoted the quantitative and functional recovery of CTLs in patients, which was associated with HCMV clearance.Conclusions. We provide robust support for the benefits of CTLs combined with antiviral drugs as a first-line therapy for treating HCMV infection and suggest that adoptively infused CTLs may stimulate the recovery of endogenous HCMV-specific immunity.