Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden.
Int Rev Immunol. 2012 Aug;31(4):289-98. doi: 10.3109/08830185.2012.692844.
CD40-mediated cancer therapy has been under development since it became clear that CD40 plays a profound role in the stimulation of adaptive immune responses. Further, CD40 signaling on tumor cells may lead to growth arrest or even apoptosis that improves therapy outcome. The therapeutic window is appealing since the immune system is selective and normal cells do not apoptose upon CD40 signaling. AdCD40L is an adenoviral-based immunostimulatory gene therapy under evaluation for its efficacy to treat cancer. Because of its nature, the adenoviral backbone will stimulate TLRs while CD40L potentiates the shifts toward Th1 type of immunity. AdCD40L has shown efficacy in various murine models, and safety studies have been performed on dog patients and in human clinical trials. AdCD40L has been used for both ex vivo gene modification of tumor cell vaccines as well as for direct intratumoral injections. Lately, an oncolytic vector has been used to further increase the eradication of solid tumors that as a consequence further boosts the release of tumor antigens and creates danger signaling in the tumor micro milieu. This review discusses the currently unfolding mechanisms of action of AdCD40L gene therapy and its possibilities to reach clinical care.
CD40 介导的癌症治疗自 CD40 在刺激适应性免疫反应中发挥深远作用变得清晰以来一直在开发中。此外，肿瘤细胞上的 CD40 信号可能导致生长停滞甚至凋亡，从而改善治疗效果。由于免疫系统具有选择性，并且正常细胞不会在 CD40 信号传导后凋亡，因此治疗窗口很有吸引力。AdCD40L 是一种基于腺病毒的免疫刺激基因治疗方法，正在评估其治疗癌症的疗效。由于其性质，腺病毒骨架在刺激 TLR 的同时，CD40L 增强了向 Th1 型免疫的转变。AdCD40L 在各种小鼠模型中显示出疗效，并且已经在狗患者和人类临床试验中进行了安全性研究。AdCD40L 已被用于肿瘤细胞疫苗的体外基因修饰以及直接肿瘤内注射。最近，使用溶瘤载体进一步增加了对实体瘤的清除，这反过来又进一步增强了肿瘤抗原的释放，并在肿瘤微环境中产生危险信号。本文讨论了 AdCD40L 基因治疗的当前作用机制及其在临床护理中的可能性。
