Development of'BioKnife', a uPA-targeted oncolytic Sendai virus to treat intractable malignancies.

恶性胸膜间皮瘤(MPM)是一种高度难治性的间皮瘤，很容易扩散到整个胸腔表面，这些细胞表达尿激酶型纤溶酶原激活剂受体(UPAR)。我们在这里检测了我们的新型和强大的重组仙台病毒(RSeV)，它显示出uPAR特异性的细胞间融合活性(rSeV/dMFct14(UPA2))，在两个独立的人原位异种移植模型中对肿瘤细胞的杀伤作用。使用BioKnife的多周期治疗有效地挽救了这些模型，并与肿瘤特异性融合和细胞凋亡有关。体外培养的MSTO-211H和H2 26细胞也有这种作用，但我们证实后者表达uPAR，而不表达uPA。值得注意的是，BioKnife感染强烈地促进了H2 26细胞uPA的释放，并且这种作用被表达C末端缺失的显性维甲酸诱导基因负性抑制物(RIG-IC)的BioKnife完全消除，这表明BioKnife依赖于BioKnife的uPA的表达是通过RIG-I/NK-κB轴来调节的，从而检测到了病毒基因组的复制。因此，这些结果表明，通过BioKnife的肿瘤细胞杀伤机制可能在治疗临床上以uPAR频繁表达为特征的MPM患者方面具有显著的潜力。

Malignant pleural mesothelioma(MPM) is highly intractable and readily spreads throughout the surface of the pleural cavity, and these cells have been shown to express urokinase-type plasminogen activator receptor(uPAR). We here examined the potential of our new and powerful recombinant Sendai virus(rSeV), which shows uPAR-specific cell-to-cell fusion activity(rSeV/dMFct14(uPA2), named“BioKnife"), for tumor cell killing in two independent orthotopic xenograft models of human. Multicycle treatment using BioKnife resulted in the efficient rescue of these models, in association with tumor-specific fusion and apoptosis. Such an effect was also seen on both MSTO-211H and H226 cells in vitro ; however, we confirmed that the latter expressed uPAR but not uPA. Of interest, infection with BioKnife strongly facilitated the uPA release from H226 cells, and this effect was completely abolished by use of either pyrrolidine dithiocarbamate or BioKnife expressing the C-terminus-deleted dominant negative inhibitor for retinoic acid-inducible gene-I(RIG-IC), indicating that BioKnife-dependent expression of uPA was mediated by the RIG-I/NK-κB axis, detecting RNA viral genome replication. Therefore, these results suggest a proof of concept that the tumor cell-killing mechanism via BioKnife may have significant potential to treat patients with MPM that is characterized by frequent uPAR expression in a clinical setting.