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 pair-matched, 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. CLINICAL TRIALS REGISTRATION NCT02985775.

中文翻译：

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供体来源的人巨细胞病毒（HCMV）特异性T细胞的一线疗法通过促进异体干细胞移植后的抗病毒免疫力降低持久性HCMV感染。

背景技术人巨细胞病毒（HCMV）感染，特别是持续性HCMV感染，是同种异体干细胞移植（allo-SCT）后发病和死亡的重要原因。抗病毒药仍然是一线治疗，但受副作用和获得性耐药性的限制。方法我们评估了供体来源的HCMV特异性细胞毒性T细胞（CTL）作为异源SCT后HCMV感染的一线治疗的安全性和有效性，并研究了其潜在机制。结果在人源化HCMV感染的小鼠中，CTL的一线疗法通过促进体内移植物衍生的内源性HCMV特异性免疫力的恢复，有效对抗了全身性HCMV感染。在一项临床试验中，与配对匹配的高风险对照人群相比，采用CTL的一线治疗显着降低了HCMV感染的持续性（2.9％vs 20.0％，P = .018）和晚期（5.7％vs 20.0％，P = .01）的发生率和持续性HCMV感染的累积发生率（危险比） [HR]，0.13； 95％置信区间[CI]，0.10-0.82； P = .02），降低了与治疗相关的1年死亡率（HR，0.15。95％CI，0.11-0.90。P= .03） ，并提高了1年总生存率（HR，6.35； 95％CI，1.05-9.00； P = .04）。此外，使用CTL的一线疗法可促进患者CTL的定量和功能恢复，这与HCMV清除率有关。结论我们为结合抗病毒药物作为治疗HCMV感染的一线疗法的CTL的益处提供了有力的支持，并建议过继输注的CTL可以刺激内源HCMV特异性免疫力的恢复。