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作者: StephenW 时间: 2019-9-6 21:33
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。
