Ad-NK4修饰的树突状细胞疫苗抗骨髓瘤免疫作用研究

Multiple myeloma (MM) remains an incurable hematologic malignant disease. Dendritic cell (DC) vaccines is expected to eliminate minimal residual disease (MRD) of tumor. However, previous studies indicated that DC vaccines did not work well in MM. It has been found recently that the hepatocyte growth factor (HGF) in marrow microenvironment of MM induces the activation of PI3K/AKT pathway and this is likely to be an important reason for the poor efficacy of DC vaccines in MM. Our preliminary study found that Ad-NK4, an inhibitor of HGF, inhibited MM cell proliferation and induced apoptosis by means of inhibiting PI3K/AKT pathway. We speculate that Ad-NK4 would modify DC function and therefore enhance DC-induced immunity against MM. In this study, we will generate DCs from MM patients’ peripheral blood and construct DC vaccines and will build a MM animal model. On this basis, we will observe the effect of Ad-NK4 on DC function and the immunity of Ad-NK4 modified DC vaccines against MM in vitro and vivo. This study will explore a new way applying DC vaccines in the immunotherapy of MM.

多发性骨髓瘤（MM）仍然是一种无法治愈的血液系统恶性肿瘤。树突状细胞（DC）疫苗被认为有望清除肿瘤微小残留病变（MRD）。但以往的研究显示DC疫苗在MM中未能发挥很好的作用。最近研究发现，MM微环境中肝细胞生长因子（HGF）诱导的PI3K/AKT通路活化可能是DC疫苗在MM中难以发挥作用的重要原因。我们前期研究发现Ad-NK4（HGF的拮抗剂）通过调控PI3K/AKT通路抑制MM细胞的增殖和诱导凋亡作用。我们推测Ad-NK4能影响DC功能而增强DC疫苗的抗MM免疫作用。本研究拟从MM患者外周血培养DC、构建DC疫苗并建立MM动物模型，通过体内外实验观察Ad-NK4对DC功能的影响及其修饰的DC疫苗抗MM免疫作用。本研究将为DC疫苗用于MM的免疫治疗探索新的策略。

本研究拟从MM患者外周血培养DC、构建DC疫苗并建立MM动物模型，通过体内外实验观察Ad-NK4对DC功能的影响及其修饰的DC疫苗抗MM免疫作用。（1）成功分离培养DC，在体外发现了Ad-NK4能调控DC的功能；（2）证实了Ad-NK4修饰的DC疫苗在体外抗MM作用；（3）成功构建MM的SCID小鼠模型，在体内证实了Ad-NK4能调控DC功能；（4）在体内证实了Ad-NK4修饰的DC疫苗在体内具有抗MM作用。本研究将为Ad-NK4用于MM的治疗探索新的策略。