Regulating cytokine function enhances safety and activity of genetic cancer therapies.
Regulating cytokine function enhances safety and activity of genetic cancer therapies.
复制标题
DOI：
10.1038/mt.2012.225
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Hannah Chen;P. Sampath;W. Hou;S. Thorne
中科院分区：
文献类型：
--
作者：
Hannah Chen;P. Sampath;W. Hou;S. Thorne
基因疗法，包括转基因免疫细胞和病毒载体，继续显示出系统可传递和靶向治疗的临床反应，第一批此类方法已被批准用于癌症治疗。其中大多数使用了细胞因子转基因。然而，全身给药后早期细胞因子的表达可能会导致毒性增加和非特异性免疫反应的诱导。此外，可能会导致过早的免疫介导的治疗清除，特别是对于基于病毒的方法。在这里，初步证实，系统递送的溶瘤病毒表达细胞因子(白介素2)或趋化因子(CCL5)导致溶瘤活性降低和免疫激活不佳，而白介素2也导致毒性增加。然而，所有这些限制都可以通过融合细胞因子或趋化因子转基因功能的外源调节来克服，方法是将一个外部可控的小的不稳定结构域融合到目的蛋白上。调节允许没有细胞因子功能的初始阶段，允许在细胞因子功能激活之前增强递送和溶瘤活性，以及随后的增强和肿瘤靶向免疫治疗活性阶段。由于细胞因子功能的这种外源性调节，溶瘤和免疫介导的作用机制都得到了优化，大大提高了治疗活性，同时显著降低了毒性。
Genetic therapies, including transfected immune cells and viral vectors, continue to show clinical responses as systemically deliverable and targeted therapeutics, with the first such approaches having been approved for cancer treatment. The majority of these employ cytokine transgenes. However, expression of cytokines early after systemic delivery can result in increased toxicity and nonspecific induction of the immune response. In addition, premature immune-mediated clearance of the therapy may result, especially for viral-based approaches. Here, it was initially verified that cytokine (interleukin (IL)2) or chemokine (CCL5) expression from a systemically delivered oncolytic virus resulted in reduced oncolytic activity and suboptimal immune activation, while IL2 also resulted in increased toxicity. However, all these limitations could be overcome through incorporation of exogenous regulation of cytokine or chemokine transgene function through fusion of a small and externally controllable destabilizing domain to the protein of interest. Regulation allowed an initial phase without cytokine function, permitting enhanced delivery and oncolytic activity before activation of cytokine function and a subsequent phase of enhanced and tumor-targeted immunotherapeutic activity. As a result of this exogenous regulation of cytokine function, both oncolytic and immune-mediated mechanisms of action were optimized, greatly enhancing therapeutic activity, while toxicity was significantly reduced.