联合GS-4774和替诺福韦治疗可改善慢性肝炎患者的HBV特异性T细

StephenW

Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis
Carolina Boni1,∗
, Harry L.A. Janssen2,∗
, Marzia Rossi1,∗
, Seung Kew Yoon3
, Andrea Vecchi1
, Valeria Barili1
, Eric M. Yoshida4
, Huy Trinh5
, Timothy C. Rodell6
, Diletta Laccabue1
, Arianna Alfieri1
, Federica Brillo1
, Paola Fisicaro1
, Greta Acerbi1
, Giuseppe Pedrazzi7
, Pietro Andreone8
, Carmela Cursaro8
, Marzia Margotti8
, Rosanna Santoro9
, Valeria Piazzolla9
, Maurizia R. Brunetto10
, Barbara Coco10
, Daniela Cavallone10
, Yang Zhao11
, Adarsh Joshi11
, Jacky Woo11
, Audrey H. Lau11
, Anuj Gaggar11
, G. Mani Subramanian11
, Benedetta Massetto11
, Scott Fung2
, Sang Hoon Ahn12
, Xiaoli Ma13
, Alessandra Mangia9
, Carlo Ferrari1,∗,'Correspondence information about the author Carlo FerrariEmail the author Carlo Ferrari
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DOI: https://doi.org/10.1053/j.gastro.2019.03.044 |


Background & Aims

One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection.
Methods

We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients.
Results

GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells.
Conclusions
In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.

StephenW

联合GS-4774和替诺福韦治疗可改善慢性肝炎患者的HBV特异性T细胞反应
Carolina Boni1，*
，Harry L.A. Janssen2，*
，Marzia Rossi1，*
，Seung Kew Yoon3
，Andrea Vecchi1
，Valeria Barili1
，Eric M. Yoshida4
，Huy Trinh5
，Timothy C. Rodell6
，Diletta Laccabue1
，Arianna Alfieri1
，Federica Brillo1
，Paola Fisicaro1
，Greta Acerbi1
，朱塞佩·佩德拉齐7
，Pietro Andreone8
，Carmela Cursaro8
，Marzia Margotti8
，Rosanna Santoro9
，Valeria Piazzolla9
，Maurizia R. Brunetto10
，Barbara Coco10
，Daniela Cavallone10
，杨昭11
，Adarsh Joshi11
，Jacky Woo11
，Audrey H. Lau11
，Anuj Gaggar11
，G。Mani Subramanian11
，Benedetta Massetto11
，Scott Fung2
，Sang Hoon Ahn12
，Xiaoli Ma13
，Alessandra Mangia9
，Carlo Ferrari1，*，'关于作者的通讯信息Carlo FerrariEmail作者Carlo Ferrari
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DOI：https：//doi.org/10.1053/j.gastro.2019.03.044 |


背景与目的

治疗慢性乙型肝炎病毒（HBV）感染的一种策略可以是增加病毒特异性T细胞的功能。我们进行了一项多中心2期研究，以评估GS-4774的安全性和有效性，GS-4774是一种基于酵母的治疗性疫苗，用于表达HBV抗原，使用替诺福韦地索普西富马酸盐（TDF）给予未治疗的慢性HBV感染患者。
方法

2014年7月至2016年8月，我们在加拿大，意大利，新西兰，罗马尼亚，韩国和美国的34个地点进行了一项开放性研究.HB表面抗原阳性的成人（HBsAg）> 6个月和水平在筛查后3个月内未接受HBV抗病毒治疗的HBVDNA≥2000IU/ mL被随机分配（1：2：2：2）至口服TDF 300 mg每日一次（n = 27;对照组）或与2,10或40个酵母单位GS-4774（n = 168），每4周皮下给药直至第20周，总共6个剂量。收集并分析血样并且患者定期接受体检。通过从基线到第24周降低HBsAg来测量功效。在来自12的T细胞中测量对HBV（干扰素γ[IFNG]，肿瘤坏死因子[TNF]，白细胞介素2 [IL2]和脱粒）的特异性应答。具有基因型D感染的HBeAg阴性患者，用来自整个HBV蛋白质组的肽刺激外周血单核细胞过夜或10天。分析T-调节细胞的频率和表型。将来自免疫细胞研究的数据与来自患者的血液样品中HBsAg，HBV DNA和丙氨酸氨基转移酶减少的数据进行比较。
结果

GS-4774安全且耐受性良好，但未显着降低HBsAg水平。在给予GS-4774而不是来自对照的患者的HBV特异性CD8 + T细胞中，与基线相比，IFNG，TNF和IL2的产生在第24周和第48周显着增加。 GS-4774对CD8 +的作用大于CD4 + T细胞，这些细胞在有或没有GS-4774的情况下完全不受TDF影响或非常弱。 GS-4774不影响T细胞对其他测试病毒的反应。在过夜刺激后，HBV核心肽诱导T细胞产生最大量的IFNG，而HBV包膜抗原不诱导应答。刺激10天后，IFNG和TNF的产生随着暴露于GS-4774的时间而增加;最高水平的反应是HBV包膜抗原，其次是核心和聚合酶。我们观察到给予GS-4774的患者在T细胞功能增加和T-调节细胞数量减少之间的相关性。
结论
在一项针对患有或不患有GS-4774的TDF的慢性HBV感染患者的2期研究中，我们发现疫苗接种可以增加暴露于抗原肽的CD8 + T细胞产生IFNG，TNF和IL2，对CD4 + T细胞几乎没有影响。 。虽然GS-4774没有降低患者的HBsAg水平，但其对CD8 + T细胞的强免疫刺激作用可能与其他抗病毒药物联合使用，以提高抗病毒免疫反应。 Clinicaltrials.gov no：NCT02174276。

StephenW

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