Therapeutic vaccination of chronic hepatitis c nonresponder patients with the peptide vaccine IC41
Therapeutic vaccination of chronic hepatitis c nonresponder patients with the peptide vaccine IC41
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DOI：
10.1053/j.gastro.2008.02.058
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发表时间：
2008-05-01
期刊：
影响因子：
29.4
通讯作者：
Manns, Michael P.
中科院分区：
文献类型：
--
作者：
Klade, Christoph S.;Wedemeyer, Heiner;Manns, Michael P.
背景与目的：IC41是一种含有7个相关丙型肝炎病毒（HCV） T细胞表位和辅助性T细胞（Th）1/Tc1佐剂聚l -精氨酸的合成肽疫苗。IC41已被证明是安全的，并能在健康志愿者中诱导分泌hcv特异性干扰素（IFN）的CD4+和CD8+ T细胞。我们的目的是研究IC41是否能够在慢性丙型肝炎患者中诱导hcv特异性t细胞反应。方法：在一项双盲II期研究中，60例hla - a2阳性的慢性HCV患者对标准治疗无反应或复发，随机分为5组，分别接种6次IC41（3个不同剂量组）、单独接种HCV肽或单独接种聚l -精氨酸。结果：IC41耐受性良好，未发生与药物相关的严重不良事件或诱发肝炎。在3个IC41疫苗组中，高达67%的患者记录到t细胞增殖，但仅在单独使用肽治疗的患者中记录到17%。ifn - γ酶联免疫斑点试验仅在IC41组中观察到应答，应答率高达42%。在所有60名患者中，有3名RNA应答者的HCV血清RNA出现短暂的bbbb1 -log下降，与最强的ifn - γ酶联免疫斑点测定值相关。结论：这项研究表明，HCV肽疫苗IC41可以在持续病毒血症的难以治疗的HCV无反应患者亚群中诱导HCV特异性Th1/Tc1反应。然而，HCV RNA的变化仅发生在单个患者中。由于最强的t细胞反应与HCV RNA下降相关，因此已启动了优化疫苗方案和联合治疗的进一步研究。
Background & Aims: IC41 is a synthetic peptide vaccine containing 7 relevant hepatitis C virus (HCV) T-cell epitopes and the T helper cell (Th)1/Tc1 adjuvant poly-L-arginine. IC41 has been shown to be safe and to induce HCV-specific interferon (IFN)-gamma-secreting CD4+ and CD8+ T cells in healthy volunteers. We aimed to investigate whether IC41 is able to induce HCV-specific T-cell responses also in chronic hepatitis C patients. Methods: Sixty HLA-A2-positive chronic HCV patients not responding to or relapsing from standard therapy were randomized in a double-blind phase II study into 5 groups to receive 6 vaccinations of IC41 (3 different dose groups), HCV peptides alone, or poly-L-arginine alone. Results: IC41 was well tolerated, and no drug-related serious adverse events or induction of hepatitis were observed. T-cell proliferation was recorded in up to 67% of patients in the 3 IC41 vaccine groups but only in 17% of patients treated with peptides alone. IFN-gamma enzyme-linked immunospot assay responses were observed exclusively in the IC41 groups with response rates up to 42%. There were 3 RNA responders with transient > 1-log declines of HCV serum RNA associated with the strongest IFN-gamma enzyme-linked immunospot assay values within all 60 patients. Conclusions: This study showed that the HCV peptide vaccine IC41 can induce HCV-specific Th1/Tc1 responses in a subset of difficult to treat HCV nonresponder patients despite persisting viremia. However, changes in HCV RNA occurred only in single patients. Because strongest T-cell responses were associated with HCV RNA decline, further studies with optimized vaccine regimens and combination therapies have been initiated.