Induction of Multi-Functional T Cells in a Phase I Clinical Trial of Dendritic Cell Immunotherapy in Hepatitis C Virus Infected Individuals

We have previously reported a world-first phase I clinical trial to treat HCV patients using monocyte-derived dendritic cells (Mo-DC) loaded with HCV-specific lipopeptides. While the brief treatment proved to be safe, it failed to reduce the viral load and induced only transient cell-mediated immune responses, measured by IFNγ ELIspot. Here we reanalysed the PBMC samples from this trial to further elucidate the immunological events associated with the Mo-DC therapy. We found that HCV-specific single- and multi-cytokine secreting T cells were induced by the Mo-DC immunotherapy in some patients, although at irregular intervals and not consistently directed to the same HCV antigen. Despite the vaccination, the responses were generally poor in quality and comprised of primarily single-cytokine secreting cells. The frequency of FOXP3+ regulatory T cells (Treg) fluctuated following DC infusion and eventually dropped to below baseline by week 12, an interesting trend suggesting that the vaccination may have resulted in a more subtle outcome than was initially apparent. Our data suggested that Mo-DC therapy induced complex immune responses in vivo that may or may not lead to clinical benefit.

本团队此前首次报道了一项全球首创的I期临床试验，采用负载丙型肝炎病毒（Hepatitis C Virus, HCV）特异性脂肽的单核细胞衍生树突状细胞（monocyte-derived dendritic cells, Mo-DC）治疗丙型肝炎患者。尽管该短程治疗被证实安全性良好，但未能降低病毒载量，且仅能诱导短暂的细胞介导免疫应答——该应答通过干扰素γ（Interferon γ, IFNγ）酶联免疫斑点试验（Enzyme-Linked ImmunoSpot, ELIspot）进行检测。本研究重新分析了该临床试验中的外周血单个核细胞（Peripheral Blood Mononuclear Cells, PBMC）样本，以进一步阐明与Mo-DC治疗相关的免疫学事件。研究发现，部分患者经Mo-DC免疫治疗后可诱导出HCV特异性的单细胞因子分泌型和多细胞因子分泌型T细胞，但此类应答出现间隔不规则，且并非始终靶向同一HCV抗原。尽管接受了该免疫接种，此类应答的整体质量仍较差，且主要以单细胞因子分泌型T细胞为主。FOXP3+调节性T细胞（regulatory T cells, Treg）的频率在DC输注后出现波动，并最终在第12周时降至基线水平以下——这一有趣的趋势提示，本次免疫接种可能带来了比最初观察到的更为微妙的结局。本研究数据表明，Mo-DC治疗可在体内诱导复杂的免疫应答，此类应答未必能带来临床获益。