在慢性乙型肝炎感染期间，HBeAg血清转换与更有效的PD-L1阻断

StephenW

JHEP Rep. 2019 Jun 28;1(3):170-178. doi: 10.1016/j.jhepr.2019.06.001. eCollection 2019 Sep.
HBeAg seroconversion is associated with a more effective PD-L1 blockade during chronic hepatitis B infection.
Ferrando-Martinez S1, Huang K1, Bennett AS1, Sterba P1, Yu L2, Suzich JA1, Janssen HLA3, Robbins SH1.
Author information

1
    Microbial Sciences, AstraZeneca, Gaithersburg, MD, USA.
2
    Statistical Sciences, AstraZeneca, Gaithersburg, MD, USA.
3
    Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada.

Abstract
Background & Aims:

Current therapies for chronic hepatitis B virus (HBV) infection control viral replication but do not eliminate the risk of progression to hepatocellular carcinoma. HBV-specific CD8 T cells are necessary for viral control, but they are rare and exhausted during chronic infection. Preclinical studies have shown that blockade of the PD-1D-L1 axis can restore HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status of patients impacts the ability of HBV-specific T cells to respond to PD-L1 blockade.
Methods:

Expression patterns of the PD-1D-L1/PD-L2 axis were analyzed in healthy donors and chronically infected patients in different clinical phases of disease. A functional assay was performed to quantify baseline HBV-specific T cell responses in chronically infected patients. Baseline responses were then compared to those attained in the presence of an anti-PD-L1 monoclonal antibody (MEDI2790).
Results:

Chronically infected patients were characterized by the upregulation of PD-1 within the T cell compartment and a concomitant upregulation of PD-L1 on myeloid dendritic cells. The upregulation was maximal in HBV e antigen (HBeAg)-positive patients but persisted after HBeAg negativization and was not restored by long-term treatment. HBV reactivity, measured as frequency of HBV-specific T cells, was significantly higher in HBeAg-negative patients with lower HBV DNA levels, independently of HBV surface antigen or alanine aminotransferase levels. Anti-PD-L1 blockade with MEDI2790 increased both the number of IFN-γ-producing T cells and the amount of IFN-γ produced per cell in 97% of patients with detectable HBV reactivity, independently of patients' clinical or treatment status.
Conclusion:

Patients with lower levels of HBV DNA and the absence of HBeAg have more intact HBV-specific T cell immunity and may benefit the most from PD-L1 blockade as a monotherapy.
Lay summary:

Hepatitis B virus (HBV)-specific T cell responses during chronic infection are weak due to the upregulation of inhibitor molecules on the immune cells. In this study we show that the inhibitory PD-1D-L1 axis is upregulated during chronic HBV infection and successful antiretroviral therapy does not restore normal levels of PD-1 and PD-L1 expression. However, in HBV e antigen-negative patients, treatment with an anti-PD-L1 antibody can increase the functionality of HBV-specific T cell responses by an average of 2-fold and is a promising new therapy for patients with chronic HBV infection.

© 2019 The Author(s).
KEYWORDS:

Chronic HBV infection; HBV cure; HBV-specific T cells; MEDI2790; PD-1 blockade; PD-L1 blockade; checkpoint inhibitor; immunotherapy
Comment in

    Is PD-1 blockade a potential therapy for HBV? [JHEP Rep. 2019]

PMID:
    32039367
PMCID:
    PMC7001560
DOI:
    10.1016/j.jhepr.2019.06.001

StephenW

JHEP代表.2019年6月28日; 1（3）：170-178。 Doi：10.1016 / j.jhepr.2019.06.001。 ECollection 2019年9月
在慢性乙型肝炎感染期间，HBeAg血清转换与更有效的PD-L1阻断有关。
Ferrando-Martinez S1，Huang K1，Bennett AS1，Sterba P1，Yu L2，Suzich JA1，Janssen HLA3，Robbins SH1。
作者信息

1
微生物科学，美国马里兰州盖瑟斯堡，阿斯利康。
2
统计科学，美国马里兰州盖瑟斯堡阿斯利康。
3
加拿大多伦多大学健康网络多伦多总医院多伦多肝病中心。

抽象
背景与目标：

当前用于慢性乙型肝炎病毒（HBV）感染的疗法可控制病毒复制，但不能消除发展为肝细胞癌的风险。 HBV特异性CD8 T细胞是控制病毒所必需的，但它们很少见，并且在慢性感染期间会耗尽。临床前研究表明，阻断PD-1：PD-L1轴可以恢复HBV特异性T细胞功能。这项研究的目的是分析患者的临床和治疗状况如何影响HBV特异性T细胞对PD-L1阻断反应的能力。
方法：

分析了PD-1：PD-L1 / PD-L2轴在不同疾病临床阶段的健康供体和慢性感染患者中的表达模式。进行功能测定以量化慢性感染患者的基线HBV特异性T细胞反应，然后将基线反应与存在抗PD-L1单克隆抗体（MEDI2790）时获得的反应进行比较。
结果：

慢性感染患者的特征是T细胞区室中PD-1的上调以及髓样树突状细胞上PD-L1的上调。 HBV e抗原（HBeAg）阳性患者的上调最大，但HBeAg阴性后仍持续上调，长期治疗未恢复。 HBV反应性（以HBV特异性T细胞的频率来衡量）在HBV DNA水平较低的HBeAg阴性患者中显着较高，与HBV表面抗原或丙氨酸转氨酶水平无关。与MEDI2790的抗PD-L1阻断可增加97％的可检测HBV反应性患者的产生IFN-γ的T细胞数量和每个细胞产生的IFN-γ数量，而与患者的临床或治疗状况无关。
结论：

HBV DNA水平较低且没有HBeAg的患者具有更完整的HBV特异性T细胞免疫力，作为单一疗法，PD-L1阻断可能会最大程度地受益。
放置摘要：

慢性感染期间，乙型肝炎病毒（HBV）特异性T细胞反应较弱，这是由于免疫细胞上抑制剂分子的上调所致。在这项研究中，我们表明在慢性HBV感染过程中，抑制性PD-1：PD-L1轴被上调，成功的抗逆转录病毒疗法不能恢复正常的PD-1和PD-L1表达水平。但是，在HBV e抗原阴性的患者中，用抗PD-L1抗体治疗可以使HBV特异性T细胞应答的功能平均增加2倍，对于慢性HBV感染的患者是有希望的新疗法。

©2019作者（s）。
关键字：

慢性HBV感染； HBV治愈； HBV特异性T细胞； MEDI2790； PD-1封锁； PD-L1封锁；检查点抑制剂；免疫疗法
发表评论

PD-1阻滞剂可能成为HBV的潜在疗法吗？ [JHEP报告.2019]

PMID：
32039367
PMCID：
PMC7001560
DOI：
10.1016 / jhepr.2019.06.001

StephenW

https://www.jhep-reports.eu/article/S2589-5559(19)30058-8/pdf