带有和不带有治疗性疫苗的尼古拉单抗的PD-1阻断剂对病毒性

StephenW

Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study [url=]Edward Gane[/url]1,,[url=]Correspondence information about the author  Edward Gane[/url]Email the author  Edward Gane
,  [url=]Daniel J. Verdon[/url]2
,  [url=]Anna E. Brooks[/url]2
,  [url=]Anuj Gaggar[/url]3
,  [url=]Anh Hoa Nguyen[/url]3
,  [url=]G. Mani Subramanian[/url]3
,  [url=]Christian Schwabe[/url]1
,  [url=]P. Rod Dunbar[/url]2





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DOI: https://doi.org/10.1016/j.jhep.2019.06.028 |

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Highlights

• •In patients with chronic HBV infection, T cell responses are inhibited, leading to an inability to control the virus.
• •One of the most common inhibitors present on exhausted T cells is PD-1, which likely contributes to T cell dysfunction.
• •A single dose of either 0.1 or 0.3 mg/kg of nivolumab, with or without GS-4774, was well tolerated and effective.
  

Background & AimsTo evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV.


MethodsIn a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24.


ResultsThere were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6–12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75–77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of −0.30 (95% CI −0.46 to −0.14) and −0.16 (95% CI −0.33 to 0.01) log10 IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log10 by the end of study. One patient, whose HBsAg went from baseline 1,173 IU/ml to undetectable at week 20, experienced an alanine aminotransferase flare (grade 3) at week 4 that resolved by week 8 and was accompanied by a significant increase in peripheral HBsAg-specific T cells at week 24.


ConclusionsIn virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient.


Lay summaryChronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB.

Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527.



Keywords:                [url=https://www.journal-of-hepatology.eu/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=Chronic hepatitis B&code=jhepat-site]Chronic hepatitis B[/url], GS-4774, Nivolumab, [url=https://www.journal-of-hepatology.eu/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=Receptor occupancy&code=jhepat-site]Receptor occupancy[/url], [url=https://www.journal-of-hepatology.eu/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=T cell response&code=jhepat-site]T cell response[/url], HBV, [url=https://www.journal-of-hepatology.eu/action/doSearch?searchType=quick&occurrences=all<rlSrch=true&searchScope=fullSite&searchText=Immune-checkpoint inhibitors&code=jhepat-site]Immune-checkpoint inhibitors[/url], Immunology

StephenW

带有和不带有治疗性疫苗的尼古拉单抗的PD-1阻断剂对病毒性抑制的慢性乙型肝炎的作用：一项初步研究
Edward Gane1，低星号，关于作者Edward Gane的通讯信息给作者Edward Gane的电子邮件
，丹尼尔·维登（Daniel J. Verdon）2
，安娜·布鲁克斯（Anna E. Brooks）2
，阿努（Anuj Gaggar）3
，Anh Hoa Nguyen3
，G。Mani Subramanian3
，克里斯汀·施瓦贝（Christian Schwabe）1
，P。Rod Dunbar2
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DOI：https：//doi.org/10.1016/j.jhep.2019.06.028 |
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强调

    •在患有慢性HBV感染的患者中，T细胞反应受到抑制，导致无法控制病毒。
    •精疲力竭的T细胞上最常见的抑制剂之一是PD-1，它可能导致T细胞功能障碍。
    •不论是否使用GS-4774，单剂量0.1或0.3μmg/ kg的纳武单抗都具有良好的耐受性和有效性。

背景与目标

为了评估增加T细胞频率和活性可能提供对乙型肝炎病毒（HBV）的持久控制的假设，我们给予了nivolumab（一种程序性死亡受体1（PD-1）抑制剂），有或没有GS-4774（一种HBV治疗性疫苗）在被病毒抑制的HBV e抗原（HBeAg）阴性的慢性HBV患者中。
方法

在Ib期研究中，患者在基线以及第4周和第0.3周时接受了0.1 mg / kg（n = 2）或0.3 mg / kg（n = 12）的单剂量nivolumab，或40个GS-4774酵母单位第4周时nivolumab的mg / kg（n = 10）。主要功效终点是尼古拉单抗后12周的平均HBV表面抗原（HBsAg）变化。通过第24周评估安全性和免疫学变化。
结果

没有3级或4级不良事件或严重不良事件。所有接受评估的患者在输注后6-12周都保留了T细胞PD-1受体的占有率，平均总和介于0.1和0.3μmg/ kg队列之间，为76％（95％CI 75-77），两组之间无显着差异。队列（p = 0.839）。接受和不接受GS-4774的0.3μmg/ kg纳武单抗的患者log10 IU / ml分别平均下降-0.30（95％CI -0.46至-0.14）和-0.16（95％CI -0.33至0.01）log10 IU / ml。患者的HBsAg较基线水平显着下降（p35 =）0.035），到研究结束时3例患者的HBsAg下降> 0.5 log10。一名患者的HBsAg在第20周时从基线1,173 20IU / ml降至无法检测到，在第4周时出现了丙氨酸氨基转移酶耀斑（3级），到第8周时消失，并伴随着外周HBsAg特异性T细胞的显着增加。第24周。
结论

在病毒抑制的HBeAg阴性患者中，检查点封锁耐受良好，并导致大多数患者的HBsAg下降和1名患者的HBsAg持续减少。
放置摘要

慢性乙型肝炎病毒感染（CHB）的特征是免疫功能异常。在患有CHB的患者中，抑制性受体（如程序性死亡受体1（PD-1））在T细胞上过度表达，从而导致肝脏中无效的免疫反应。本文中，我们显示了PD-1抑制剂nivolumab对于治疗被病毒抑制的CHB患者是安全有效的。

澳大利亚新西兰临床试验注册处（http://www.anzctr.org.au/）编号：ACTRN12615001133527。
关键字：
慢性乙型肝炎，GS-4774，Nivolumab，受体占用，T细胞反应，HBV，免疫检查点抑制剂，免疫学

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