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标题: HBeAg血清学转换与慢性乙型肝炎感染期间更有效的PD-L1阻断有 [打印本页]

作者: StephenW 时间: 2019-7-19 13:59 标题: HBeAg血清学转换与慢性乙型肝炎感染期间更有效的PD-L1阻断有

HBeAg seroconversion is associated with a more effective PD-L1 blockade during chronic Hepatitis B infection
Sara Ferrando-Martinez1, low asterisk, 'Correspondence information about the author Sara Ferrando-MartinezEmail the author Sara Ferrando-Martinez
, Kelly Huang1
, Angie Snell Bennett1
, Patricia Sterba1
, Li Yu2
, JoAnn A Suzich1
, Harry L.A. Janssen3
, Scott H. Robbins1
Open Access
DOI: https://doi.org/10.1016/j.jhepr.2019.06.001

Highlights

•

Upregulation of the PD-1: PD-L1 axis is more profound in HBeAg-positive samples but does not normalize in HBeAg-negative or patients under antiviral therapy and successful viral suppression.
•

HBV-specific T cell reactivity is higher in HBeAg-negative patients with low HBV DNA levels independently of ALT or HBsAg levels.
•

97% of HBV-reactive patients respond to anti-PD-L1 blockade with MEDI2790 independent of their clinical status.

Abstract

Background and aims.

Current therapies for chronic 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 of the TPS functionality can be improved by HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status impacts the ability of HBV-specific T cells to respond to PD-L1 blockade.
Methods

Expression patterns of the PD-1

D-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 a blocking 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 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 HBsAg or ALT levels. Anti-PD-L1 blockade with MEDI2790 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 their clinical and 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.

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 PD-1

D-L1 axis is upregulated during chronic HBV infection and successful antiretroviral therapy does not The normal level of PD-1 and PD-L1 expression. However, in HBeAg-negative patients, treatment with an anti-PD-L1 antibody can increase the functionality of HBV-specific T cell response by an average of 2-fold and is a promising new therapy to treat patients with chronic HBV infection.

作者: StephenW 时间: 2019-7-19 13:59

HBeAg血清学转换与慢性乙型肝炎感染期间更有效的PD-L1阻断有关
Sara Ferrando-Martinez1，低星号，'关于作者Sara Ferrando-Martinez的通讯信息Email作者Sara Ferrando-Martinez
，Kelly Huang1
，Angie Snell Bennett1
，Patricia Sterba1
，李宇2
，JoAnn A Suzich1
，Harry L.A. Janssen3
，Scott H. Robbins1
开放存取
DOI：https：//doi.org/10.1016/j.jhepr.2019.06.001

强调

•

PD-1的上调：PD-L1轴在HBeAg阳性样品中更为显着，但在HBeAg阴性或抗病毒治疗和病毒抑制成功的患者中未正常化。
•

HBV特异性T细胞反应性在HBeAg阴性患者中较高，HBV DNA水平低，与ALT或HBsAg水平无关。
•

97％的HBV反应患者对MEDI2790的抗PD-L1阻断有反应，与其临床状态无关。

抽象

背景和目标。

目前用于慢性HBV感染的疗法控制病毒复制但不消除进展为肝细胞癌的风险。 HBV特异性CD8 T细胞是病毒控制所必需的，但它们在慢性感染期间很少见并且耗尽。临床前研究表明，通过HBV特异性T细胞功能可以改善对TPS功能性PD的阻断。本研究的目的是分析临床和治疗状态如何影响HBV特异性T细胞对PD-L1阻断的反应能力。
方法

在疾病的不同临床阶段的健康供体和慢性感染患者中分析PD-1：PD-L1 / PD-L2轴的表达模式。进行功能测定以定量慢性感染患者中的基线HBV特异性T细胞应答然后将基线应答与在阻断性抗PD-L1单克隆抗体（MEDI2790）存在下获得的那些进行比较。
结果

慢性感染患者的特征在于T细胞区室内PD-1的上调和伴随的骨髓树突细胞上PD-L1的上调。 HBeAg阳性患者的上调最多，但HBeAg阴性后持续上调，长期治疗无法恢复。 HBV反应性（以HBV特异性T细胞的频率测量）显着高于HBeAg阴性的HBV DNA水平较低的患者，与HBsAg或ALT水平无关。使用MEDI2790的抗PD-L1阻断97％具有可检测的HBV反应性的患者中产生IFN-γ的T细胞的数量和每个细胞产生的IFN-γ的量，与其临床和治疗状态无关。
结论

HBV DNA水平较低且HBeAg缺失的患者具有更完整的HBV特异性T细胞免疫力，并且作为单一疗法可能从PD-L1阻断中受益最多。

LAY Summary。

由于免疫细胞上的抑制剂分子的上调，慢性感染期间的HBV特异性T细胞应答很弱。在这项研究中，我们显示PD-1：PD-L1轴在慢性HBV感染期间上调，并且成功的抗逆转录病毒治疗没有正常水平的PD-1和PD-L1表达。然而，在HBeAg阴性患者中，用抗PD-L1抗体治疗可使HBV特异性T细胞应答的功能平均增加2倍，并且是治疗慢性HBV感染患者的有希望的新疗法。

作者: StephenW 时间: 2019-7-19 13:59

https://www.jhep-reports.eu/arti ... 19)30058-8/fulltext

作者: SK蜗牛 时间: 2019-7-20 23:42

PD-L1抑制剂，确实是一种比较好的免疫药物，而且是已经面试很多年的了，不过目前价格太贵了，国内目前也有好多款PD-L1抑制剂要上市，希望可以把价格降低下来

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