Oncology, Faculty of Health and Medical Sciences, University of Surrey, Leggett Building, Guildford, Surrey, GU2 7WG, UK.
Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK.
Cancer Gene Ther. 2018 Jun;25(5-6):148-160. doi: 10.1038/s41417-018-0011-8. Epub 2018 May 3.
There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination.
目前有许多溶瘤病毒正在癌症患者中进行临床试验评估，其中一种药物 Talimogene laherparepvec 已被批准用于治疗恶性黑色素瘤。这一进展突出了这种治疗模式的巨大临床潜力，目前的重点是将这些药物与传统抗癌药物或增强肿瘤微环境中病毒复制从而溶瘤的药物联合使用。我们基于 mTOR 抑制剂可能增强病毒溶瘤作用的潜在机制，评估了呼肠孤病毒与雷帕霉素在 B16F10 细胞（一种恶性黑色素瘤的小鼠模型）中的联合作用。雷帕霉素没有免疫调节作用，因为它对 C57/black 6 小鼠产生抗呼肠孤病毒中和抗体反应没有影响。呼肠孤病毒（增加 G0/G1 期分数）的细胞周期作用不受雷帕霉素的同时或序贯暴露影响。然而，如果在呼肠孤病毒之前或同时给予雷帕霉素，雷帕霉素会抑制病毒复制，并类似地减少呼肠孤病毒诱导的细胞凋亡（Annexin V/PI 和 caspase 3/7 激活研究）。我们发现，无论是在体外还是体内，这种联合用药都有明显的协同抗肿瘤作用，而这种协同作用在体外的实验条件下仅仅取决于药物的使用顺序。总之，我们已经证明了呼肠孤病毒和雷帕霉素联合应用的协同抗肿瘤疗效。
