The Division of Cancer Biology and Biologic Therapeutics Center, Department of Radiation Oncology, School of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8224, St. Louis, MO, 63110, USA.
Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, PO Box 7607, Holy Makkah, Saudi Arabia.
J Ovarian Res. 2019 Feb 15;12(1):18. doi: 10.1186/s13048-019-0493-5.
Virotherapy represents a promising approach for ovarian cancer. In this regard, conditionally replicative adenovirus (CRAd) has been translated to the context of human clinical trials. Advanced design of CRAds has sought to exploit their capacity to induce anti-tumor immunization by configuring immunoregulatory molecule within the CRAd genome. Unfortunately, employed murine xenograft models do not allow full analysis of the immunologic activity linked to CRAd replication.
We developed CRAds based on the Ad5/3-Delta24 design encoding cytokines. Whereas the encoded cytokines did not impact adversely CRAd-induced oncolysis in vitro, no gain in anti-tumor activity was noted in immune-incompetent murine models with human ovarian cancer xenografts. On this basis, we explored the potential utility of the murine syngeneic immunocompetent ID8 ovarian cancer model. Of note, the ID8 murine ovarian cancer cell lines exhibited CRAd-mediated cytolysis. The use of this model now enables the rational design of oncolytic agents to achieve anti-tumor immunotherapy.
Limits of widely employed murine xenograft models of ovarian cancer limit their utility for design and study of armed CRAd virotherapy agents. The ID8 model exhibited CRAd-induced oncolysis. This feature predicate its potential utility for the study of CRAd-based virotherapy agents.
溶瘤病毒治疗代表了一种很有前途的卵巢癌治疗方法。在这方面，条件复制型腺病毒（CRAd）已被转化为人类临床试验的范畴。CRAd 的高级设计旨在通过在 CRAd 基因组中配置免疫调节分子来利用其诱导抗肿瘤免疫的能力。不幸的是，所采用的鼠异种移植模型不允许对与 CRAd 复制相关的免疫活性进行全面分析。
我们基于 Ad5/3-Delta24 设计开发了编码细胞因子的 CRAds。虽然编码的细胞因子对 CRAd 诱导的体外溶瘤作用没有不利影响，但在具有人卵巢癌异种移植物的免疫功能低下的鼠模型中，没有观察到抗肿瘤活性的增加。在此基础上，我们探讨了鼠同源免疫 competent ID8 卵巢癌模型的潜在用途。值得注意的是，ID8 鼠卵巢癌细胞系表现出 CRAd 介导的细胞溶解。该模型的使用现在能够为设计和研究武装 CRAd 溶瘤病毒治疗剂提供合理的设计。
广泛应用的卵巢癌鼠异种移植模型的局限性限制了它们在武装 CRAd 溶瘤病毒治疗剂的设计和研究中的应用。ID8 模型表现出 CRAd 诱导的溶瘤作用。这一特征预示着它在研究基于 CRAd 的溶瘤病毒治疗剂方面具有潜在的应用价值。
