First-Line Therapy with Donor Derived HCMV-Specific T Cells Reduce Persistent HCMV Infection after Allogenic Stem Cell Transplantation
Authors: Zhao Xiangyu , Pei Xuying , Huang Xiaojun , Chang Ying-Jun , Xu Lanping , Zhang Xiaohui , Liu Kaiyan 
Published: October 2019

Abstract
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 mainstay of treatment and are recommend as the first-line therapy for HCMV. However, drugs are associated with significant toxicity, and their efficacy is limited in the absence of cell-mediated immunity. In recent years, adoptive immunotherapy with HCMV-specific T cells (CTLs) has been developed as an alternative option for HCMV, and data from previous studies have indicated that infusion of CTLs at early-stage of HCMV infection may have better benefits compared to salavage therapy. However, because CTLs remains time consuming and cost-intensive, so far there have no reports of first-line therapy with CTLs for HCMV infection, and the mechanisms driving the sustained antiviral immunity induced by adoptive T cells transfer remain undetermined. Our previous study had demonstrated that patients with acute graft-versus-host disease (aGVHD) were at high risk to develop persistent HCMV infection. Therefore, in the current study, we selected patients who developed aGVHD before HCMV reactivated and started CTLs generation in advance. This risk-stratified measure successfully selected patients who had high risk resisting to conventional anti-HCMV therapy , and spared low risk patients as well, making it feasible and financially viable to use CTLs as a first-line therapy.
Aims: To provide robust support for the safety and efficacy of CTLs given as a first-line therapy for HCMV infection after allo-SCT, and gain some insight into the underlying mechanisms.
Methods: Firstly, using humanized HCMV infected mice model, we explored where the adoptive transferred CTLs cells trafficked, evaluated the antiviral efficacy of CTLs and investigated the recovery of HCMV-specific immunity after T cell transfer. Secondly, we conducted a prospective clinical trial enrolled 35 allo-SCT patients who diagnosed with acute GVHD and had high risk developing persistent HCMV infection, intervened with antiviral agents combined with CTLs as first-line therapy and evaluated the long-term safety and durability of antiviral responses. As controls, we selected a cohort of 70 high-risk patients as well as another cohort of 70 low-risk patients who only received antiviral agents as first-line therapy without CTLs. We also evaluated the immune response after infusion and analyzed the association between immune recovery and HCMV clearance.
Results: i) In humanized HCMV infection mice, adoptive infused CTLs had the ability to homing to organs, and effectively combated systemic HCMV infection by promoting the restoring of stem cell derived endogenous HCMV-specific immunity. ii) In clinical trial, first-line therapy with CTLs significantly reduced the rate (2.86% vs. 20.00%, P=0.018) and the cumulative incidence (HR=7.60, 95%CI=1.22-10.15, P=0.020) of persistent HCMV infection, and showed a lower one-year treatment related mortality (TRM) (HR=6.83, 95%CI=1.16-8.90, P=0.030) and a better one-year overall survival (OS) (HR=6.35, 95%CI=1.05-9.00, P=0.040) compared to high-risk control cohort. The cumulative incidence of persistent HCMV infection, one-year TRM and OS in CTL cohort were comparable to those in low-risk control cohort. Moreover, first-line therapy with CTLs promoted the quantitative and functional recovery of CTLs in patients, which was associated with HCMV clearance.
Conclusion: In this study, we firstly demonstrated the safety and efficacy of CTLs administration as a first-line therapy for HCMV infection in humanized HCMV infection mice, and in a large clinical cohort study. The data provided robust support for the benefits of donor derived CTLs in treating HCMV infection as a first-line therapy, and suggested that infused CTLs might probably stimulate the recovery of donor derived HCMV-specific immunity. This trial was registered at www.clinicaltrials.gov as #NCT02985775.
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Disclosures
No relevant conflicts of interest to declare.