Cancer Gene Therapy Group, Molecular Cancer Biology Program, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Finland.
Int J Cancer. 2012 Jul 1;131(1):253-63. doi: 10.1002/ijc.26370. Epub 2011 Sep 14.
Conventional cancer treatments often have little impact on the course of advanced pancreatic cancer. Although cancer gene therapy with adenoviruses is a promising developmental approach, the primary receptor is poorly expressed in pancreatic cancers which might compromise efficacy and thus targeting to other receptors could be beneficial. Extended stealth delivery, combination with standard chemotherapy or circumvention of host antiadenoviral immune response might improve efficacy further. In this work, capsid-modified adenoviruses were studied for transduction of cell lines and clinical normal and tumor tissue samples. The respective oncolytic viruses were tested for oncolytic activity in vitro and in vivo. Survival was studied in a peritoneally disseminated pancreas cancer model, with or without concurrent gemcitabine while silica implants were utilized for extended intraperitoneal virus delivery. Immunocompetent mice and Syrian hamsters were used to study the effect of silica mediated delivery on antiviral immune responses and subsequent in vivo gene delivery. Capsid modifications selectively enhanced gene transfer to malignant pancreatic cancer cell lines and clinical samples. The respective oncolytic viruses resulted in increased cell killing in vitro, which translated into a survival benefit in mice. Early proinfammatory cytokine responses and formation of antiviral neutralizing antibodies was partially avoided with silica implants. The implant also shielded the virus from pre-existing neutralizing antibodies, while increasing the pancreas/liver gene delivery ratio six-fold. In conclusion, capsid modified adenoviruses would be useful for testing in pancreatic cancer trials. Silica implants might increase the safety and efficacy of the approach.
传统的癌症治疗方法对晚期胰腺癌的治疗效果往往不大。虽然腺病毒的癌症基因治疗是一种很有前途的发展方法，但主要受体在胰腺癌中的表达水平较低，这可能会影响疗效，因此针对其他受体可能会更有益。延长隐形传递、与标准化疗联合或规避宿主抗腺病毒免疫反应可能会进一步提高疗效。在这项工作中，研究了衣壳修饰的腺病毒在细胞系和临床正常及肿瘤组织样本中的转导。相应的溶瘤病毒在体外和体内进行了溶瘤活性测试。在腹膜扩散性胰腺癌模型中，研究了生存情况，同时或不伴有顺铂治疗，而使用硅胶植入物进行延长的腹腔内病毒传递。免疫功能正常的小鼠和叙利亚仓鼠用于研究硅胶介导的传递对抗病毒免疫反应的影响，以及随后的体内基因传递。衣壳修饰选择性地增强了对恶性胰腺癌细胞系和临床样本的基因转移。相应的溶瘤病毒在体外导致细胞杀伤增加，这转化为小鼠的生存获益。早期的促炎细胞因子反应和抗病毒中和抗体的形成部分被硅胶植入物避免了。该植入物还能保护病毒免受预先存在的中和抗体的影响，同时将胰腺/肝脏的基因传递比例增加了六倍。总之，衣壳修饰的腺病毒将有助于在胰腺癌试验中进行测试。硅胶植入物可能会提高这种方法的安全性和疗效。
