使用Nivolumab进行抗PD-1阻断，有和没有治疗性疫苗接种治疗病

StephenW

J Hepatol. 2019 Jul 12. pii: S0168-8278(19)30400-3. doi: 10.1016/j.jhep.2019.06.028. [Epub ahead of print]
Anti-PD-1 Blockade with Nivolumab with and without Therapeutic Vaccination for Virally Suppressed Chronic Hepatitis B: A Pilot Study.
Gane E1, Verdon DJ2, Brooks AE2, Gaggar A3, Nguyen AH3, Subramanian GM3, Schwabe C4, Dunbar PR2.
Author information

1
    Auckland Clinical Studies, Auckland, New Zealand. Electronic address: [email protected].
2
    School of Biological Sciences, and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
3
    Gilead Sciences, Inc., Foster City, California, USA.
4
    Auckland Clinical Studies, Auckland, New Zealand.

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.

Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:

Chronic hepatitis B; GS-4774; T cell response; nivolumab; receptor occupancy

PMID:
    31306680
DOI:
    10.1016/j.jhep.2019.06.028

StephenW

J Hepatol。 2019年7月12日.pii：S0168-8278（19）30400-3。 doi：10.1016 / j.jhep.2019.06.028。 [印刷前的电子版]
使用Nivolumab进行抗PD-1阻断，有和没有治疗性疫苗接种治疗病毒性慢性乙型肝炎：一项试验性研究。
Gane E1，Verdon DJ2，Brooks AE2，Gaggar A3，Nguyen AH3，Subramanian GM3，Schwabe C4，Dunbar PR2。
作者信息

1
    奥克兰临床研究，新西兰奥克兰。电子地址：[email protected]。
2
    新西兰奥克兰大学生物科学学院和莫里斯威尔金斯中心。
3
    Gilead Sciences，Inc.，Foster City，California，USA。
4
    奥克兰临床研究，新西兰奥克兰。

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。

版权所有©2019。Elsevier B.V.
关键词：

慢性乙型肝炎; GS-4774; T细胞反应; nivolumab;受体占有率

结论：
    31306680
DOI：
    10.1016 / j.jhep.2019.06.028

齐欢畅

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

齐欢畅

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

hp121

说句要求过高的话

现在HBSAG能降低的药真不少了，关键是实质性治愈