Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study

无容量 乙型肝炎表面抗原 医学 不利影响 乙型肝炎病毒 HBeAg 乙型肝炎 胃肠病学 接种疫苗 免疫疗法 免疫学 内科学 癌症 病毒
作者
Edward Gane,Daniel J. Verdon,Anna E. S. Brooks,Anuj Gaggar,Anh H. Nguyen,G. Mani Subramanian,Christian Schwabe,P. Rod Dunbar
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:71 (5): 900-907 被引量:278
标识
DOI:10.1016/j.jhep.2019.06.028
摘要

To 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.In 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.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 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.In 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.Chronic 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.
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