Auckland Clinical Studies, Auckland, New Zealand.
School of Biological Sciences, and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
J Hepatol. 2019 Nov;71(5):900-907. doi: 10.1016/j.jhep.2019.06.028. Epub 2019 Jul 12.
BACKGROUND & 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 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. METHODS: 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. 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 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log 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. 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 1 patient. LAY SUMMARY: 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.
背景与目的：为了评估以下假说，即增加 T 细胞频率和活性可能为乙型肝炎病毒（HBV）提供持久控制，我们在 HBV e 抗原（HBeAg）阴性慢性 HBV 病毒抑制患者中，给予nivolumab（一种程序性死亡受体 1（PD-1）抑制剂）联合或不联合 GS-4774（一种 HBV 治疗性疫苗）。 方法：在一项 Ib 期研究中，患者接受了单次 0.1mg/kg（n=2）或 0.3mg/kg（n=12）nivolumab，或基线和第 4 周时 40 个酵母单位的 GS-4774，以及第 4 周时 0.3mg/kg 的 nivolumab（n=10）。主要疗效终点是 nivolumab 治疗 12 周后 HBV 表面抗原（HBsAg）的平均变化。安全性和免疫变化在第 24 周评估。 结果：没有 3 级或 4 级不良事件或严重不良事件。所有评估患者在输注后 6-12 周保留 T 细胞 PD-1 受体占有率，0.1 和 0.3mg/kg 队列的平均总占有率为 76%（95%CI 75-77%），并且两个队列之间没有观察到显著差异（p=0.839）。接受 0.3mg/kg nivolumab 联合或不联合 GS-4774 的患者分别有 -0.30（95%CI -0.46 至 -0.14）和 -0.16（95%CI -0.33 至 0.01）log IU/ml 的平均 HBsAg 下降。患者的 HBsAg 从基线开始出现显著下降（p=0.035），其中 3 名患者在研究结束时 HBsAg 下降超过 0.5 log。一名 HBsAg 从基线的 1173IU/ml 降至不可检测的患者在第 4 周时出现丙氨酸氨基转移酶（ALT）爆发（3 级），在第 8 周时得到解决，并在第 24 周时外周 HBsAg 特异性 T 细胞显著增加。 结论：在病毒抑制的 HBeAg 阴性患者中，检查点阻断是耐受良好的，并导致大多数患者的 HBsAg 下降，1 名患者持续 HBsAg 丢失。 简要结论：慢性乙型肝炎病毒感染（CHB）的特征是免疫功能失调。在 CHB 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，导致肝脏中无效的免疫反应。在此，我们表明 PD-1 抑制剂 nivolumab 对治疗病毒抑制的 CHB 患者是安全有效的。澳大利亚新西兰临床试验注册中心（http://www.anzctr.org.au/）编号：ACTRN12615001133527。
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