Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study
Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study
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DOI：
10.1016/j.jhep.2019.06.028
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发表时间：
2019-11-01
影响因子：
25.7
通讯作者：
Rod Dunbar, P.
中科院分区：
文献类型：
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作者：
Gane, Edward;Verdon, Daniel J.;Rod Dunbar, P.
背景和目标：为了评估增加T细胞频率和活性可以提供对B型肝炎病毒（HBV）的持久控制的假设，我们在具有HBV e抗原（HBeAg）阴性的慢性HBV的病毒抑制患者中给予nivolumab（程序性死亡受体1（PD-1）抑制剂），伴随或不伴随GS-4774（HBV治疗性疫苗）。在Ib期研究中，患者接受单剂量的纳武单抗0.1 mg/kg（n = 2）或0.3 mg/kg（n = 12），或40酵母单位的GS-4774和0.3 mg/kg的纳武单抗（n = 10）。主要疗效终点是纳武利尤单抗治疗后12周HBV表面抗原（HBsAg）的平均变化。至24周评估安全性和免疫学变化。结果：未发生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受体结合率，0.1和0.3 mg/kg队列的平均总结合率为76%（95% CI 75-77），队列间未观察到显著差异（p = 0.839）。接受0.3 mg/kg nivolumab（不含和含GS-4774）的患者的平均降幅分别为-0.30（95% CI -0.46至-0.14）和-0.16（95% CI -0.33至0.01）log（10）IU/ml。患者的HBsAg较基线水平显著下降（p = 0.035），其中3例患者在研究结束时下降>0.5 log（10）。1例患者的HBsAg从基线1，173 IU/ml降至第20周时检测不到，第4周时发生丙氨酸氨基转移酶爆发（3级），第8周时消退，第24周时伴有外周血HBsAg特异性T细胞显著增加。在病毒抑制的HBeAg阴性患者中，检查点阻断耐受性良好，导致大多数患者HBsAg下降，1例患者持续HBsAg丢失。慢性B型肝炎病毒感染（CH B）的特征是免疫应答功能障碍。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抑制剂纳武单抗对于治疗病毒抑制的CHB患者是安全有效的。(C)2019由Elsevier B. V.代表欧洲肝脏研究协会发表。
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(10) IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log(10) 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. (C) 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.