Working Peter K, Lin Andy, Borellini Flavia
Cell Genesys, Inc., South San Francisco, CA 94080, USA.
Oncogene. 2005 Nov 21;24(52):7792-801. doi: 10.1038/sj.onc.1209045.
Oncolytic adenoviruses have been considered for use as anticancer therapy for decades, and numerous means of conferring tumor selectivity have been developed. As with any new therapy, the trip from the laboratory bench to the clinic has revealed a number of significant development hurdles. Viral therapies are subject to specific regulations and must meet a variety of well-defined criteria for purity, potency, stability, and product characterization prior to their use in the clinic. Published regulatory guidelines, although developed specifically for biotechnology-derived products, are applicable to the production of oncolytic adenoviruses and other cell-based products, and they should be consulted early during development. Most importantly, both the manufacturing process and the development of characterization and release assays should be science-driven, use the best available science and technology, and must consider the unique nature of the product: a living, and mutatable, virus. Potentially significant impacts on product quality and safety stem from the possibility of genetic instability related to over-engineering the viruses (as evidenced by their recombination and/or occasional reversion to wild-type virus during manufacturing). This report provides examples of some of the critical components affecting the development and production of clinical grade material and summarizes the significant progress made in recent years.
几十年来，溶瘤腺病毒一直被视为一种抗癌治疗手段，并且已经开发出多种赋予肿瘤选择性的方法。与任何新疗法一样，从实验室工作台到临床的过程揭示了许多重大的发展障碍。病毒疗法受到特定法规的约束，并且在临床使用之前必须满足关于纯度、效力、稳定性和产品特性的各种明确标准。已发布的监管指南虽然是专门为生物技术衍生产品制定的，但适用于溶瘤腺病毒和其他基于细胞的产品的生产，在开发早期就应该参考这些指南。最重要的是，制造过程以及表征和放行检测的开发都应以科学为驱动，采用现有的最佳科学技术，并且必须考虑产品的独特性质：一种有生命且可变异的病毒。与对病毒过度设计相关的基因不稳定性（如在制造过程中它们发生重组和/或偶尔回复为野生型病毒所证明的）可能会对产品质量和安全性产生潜在的重大影响。本报告提供了一些影响临床级材料开发和生产的关键组件的示例，并总结了近年来取得的重大进展。
