使用Nivolumab进行抗PD-1阻断，有和没有治疗性疫苗接种的病毒

StephenW

Anti-PD-1 Blockade with Nivolumab with and without Therapeutic Vaccination for Virally Suppressed Chronic Hepatitis B: A Pilot Study
Edward Gane1,low asterisk,'Correspondence information about the author Edward GaneEmail the author Edward Gane
, Daniel J. Verdon2
, Anna E. Brooks2
, Anuj Gaggar3
, Anh Hoa Nguyen3
, G. Mani Subramanian3
, Christian Schwabe1
, P. Rod Dunbar2
PlumX Metrics
DOI: https://doi.org/10.1016/j.jhep.2019.06.028

Highlights

    •In patients with chronic hepatitis B virus (HBV) infection, T-cell immune responses are inhibited, leading to an inability to control or eliminate the virus.
    •One of the most common inhibitors present in these patients is programmed death receptor 1 (PD-1), especially on T-cells within the liver.
    •In this study, we assessed the efficacy and safety of a single dose of either 0.1 or 0.3 mg/kg of nivolumab, an inhibitor of PD-1, with or without GS-4774, a therapeutic vaccine, in patients with chronic HBV.

Abstract
Background and Aims

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

 In a Phase 1b study, patients received either 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 HBsAg 12 weeks after nivolumab. Safety and immunologic changes were assessed through Week 24.
Results

 There 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,-0.14) and -0.16 (95% CI, -0.33,0.01) log10 IU/mL, respectively. Patients showed significant HBsAg declines from baseline (p=0.035) with three patients experiencing declines of >0.5 log10 by end of study. One patient, whose HBsAg went from baseline 1173 IU/mL to undetectable at Week 20, experienced an ALT flare (grade 3) at Week 4 that resolved by Week 8 accompanied by a significant increase in peripheral HBsAg-specific T-cells at Week 24.
Conclusions

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

Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527
Abbreviations:
HBV (hepatitis B virus), HBsAg (hepatitis B surface antigen), cccDNA (covalently closed circular DNA), PD-1 (programmed death receptor 1), SAE (serious adverse event), AE (adverse event), HBeAg (hepatitis B e antigen), YU (yeast units), PBMC (peripheral blood mononuclear cells), MMRM (mixed-effect model for repeated measures), LSM (least square means), CI (confidence interval), ALT (alanine aminotransferase)
Keywords:
Chronic hepatitis B, GS-4774, nivolumab, receptor occupancy, T cell response

StephenW

使用Nivolumab进行抗PD-1阻断，有和没有治疗性疫苗接种的病毒性慢性乙型肝炎：一项试点研究
Edward Gane1，低星号，'作者信息关于作者Edward GaneEmail的作者Edward Gane
，Daniel J. Verdon2
，Anna E. Brooks2
，Anuj Gaggar3
，Anh Hoa Nguyen3
，G。Mani Subramanian3
，Christian Schwabe1
，P。Rod Dunbar2
PlumX度量标准
DOI：https：//doi.org/10.1016/j.jhep.2019.06.028

强调

    •在慢性乙型肝炎病毒（HBV）感染患者中，T细胞免疫反应受到抑制，导致无法控制或消除病毒。
    •这些患者中最常见的抑制剂之一是程序性死亡受体1（PD-1），尤其是肝脏内的T细胞。
    •在本研究中，我们评估了单剂量0.1或0.3 mg / kg nivolumab（一种PD-1抑制剂）的有效性和安全性，有或没有GS-4774，一种治疗性疫苗，用于慢性HBV患者。

抽象
背景和目的

为了评估增加T细胞频率和活性可以提供乙型肝炎病毒（HBV）持久控制的假设，我们给予nivolumab，一种PD-1抑制剂，含或不含GS-4774，一种HBV治疗性疫苗，用于病毒抑制HBeAg阴性慢性HBV患者。
方法

在1b期研究中，患者接受单剂量的nivolumab 0.1 mg / kg（n = 2）或0.3 mg / kg（n = 12），或40个酵母单位的GS-4774基线和第4周和0.3 mg在第4周时的/ kg nivolumab（n = 10）。主要疗效终点是nivolumab后12周HBsAg的平均变化。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。所有评估的患者在输注后6-12周保留T细胞PD-1受体占有率，平均总数为0.1和0.3mg / kg组群为76％（95％CI 75,77），并且未观察到显着差异队列之间（p = 0.839）。接受0.3mg / kg nivolumab且不含和使用GS-4774的患者的平均下降分别为-0.30（95％CI，-0.46，-0.14）和-0.16（95％CI，-0.33,0.01）log10IU / mL。患者显示HBsAg显着低于基线水平（p = 0.035），三名患者在研究结束时下降> 0.5 log10。一名患者的HBsAg从基线1173 IU / mL升至第20周无法检测到，在第4周时出现ALT突发（3级），第8周消退，伴有第24周外周HBsAg特异性T细胞显着增加。
结论

在病毒抑制的HBeAg阴性患者中，检查点阻滞耐受性良好，导致大多数患者HBsAg下降，一名患者HBsAg持续减少。

澳大利亚新西兰临床试验注册处（http://www.anzctr.org.au/）编号：ACTRN12615001133527
缩写：
HBV（乙型肝炎病毒），HBsAg（乙型肝炎表面抗原），cccDNA（共价闭合环状DNA），PD-1（程序性死亡受体1），SAE（严重不良事件），AE（不良事件），HBeAg（乙型肝炎） e抗原），YU（酵母单位），PBMC（外周血单核细胞），MMRM（重复测量的混合效应模型），LSM（最小二乘法），CI（置信区间），ALT（丙氨酸氨基转移酶）
关键词：
慢性乙型肝炎，GS-4774，nivolumab，受体占有率，T细胞反应

dxd2017

回复 StephenW 的帖子

这个感觉可行性是有的，因为试验里的剂量是治疗癌症剂量的十分之一。
治疗癌症是3mg/kg，这个试验最多的是0.3mg/kg。
价格也是治疗癌症的十分之一。
副作用可能也只有几分之一，可以耐受。
价格和剂量的介绍

newchinabok

这个试验在做，看以后试验转阴结果

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