Evaluation of efficacy and safety of gene-chemotherapy for biliary cancers using oncolytic adenovirus armed with UPRT

溶瘤病毒为癌症治疗提供了巨大的希望，但必须克服宿主的抗病毒免疫才能发挥其疗效。在这项研究中，我们证明了表达尿嘧啶磷酸核糖基转移酶(UPRT)的溶瘤腺病毒(OAD)的有效性和安全性，该病毒可显著增强癌细胞对5-氟尿嘧啶的敏感性，并在有或不存在预先存在的免疫的叙利亚仓鼠中，通过大剂量或临床批准的安全剂量的免疫抑制剂环磷酰胺(CP)进一步增强这一效果。这是第一项通过CP增强携带治疗性基因的OAD在允许的免疫活性动物中的有效性的研究，表明CP有能力克服抗病毒免疫的障碍，进行有效的病毒基因治疗。

Oncolytic viruses offer great promise as cancer therapeutics, but host antiviral immunity must be overcome for their efficacy. In this study, we demonstrated the efficacy and safety of an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), which greatly enhances the sensitivity of cancer cells to 5-fluorouracil, and further enhancement of this efficacy by a high-dose or clinically-approved safe dose of the immunosuppressive agent cyclophosphamide (CP) in Syrian hamsters with or without preexisting immunity. This is the first study demonstrating enhancement by CP of the efficacy of an OAd armed with a therapeutic gene in Ad-permissive immunocompetent animals, indicating the ability of CP to overcome the hurdle of antiviral immunity for effective virus-gene therapy.