关于细胞治疗产品药学研发中成瘤性和致瘤性风险评价与控制的思考

Chemistry, Manufacturing and Controls Considerations for Tumorigenicity and Oncogenicity on Cellular Therapy Products

摘要: 随着包括免疫细胞、干细胞等细胞治疗新兴生物技术产品临床转化加速，其成瘤性及致瘤性安全风险备受关注。由不同厂家生产的不同类型的细胞治疗产品在原材料、生产工艺等方面差异较大，需根据具体风险评估情况制定相应策略。相较于已终末分化的体细胞产品，具有多向分化的干细胞成瘤性风险较高，生产工艺如培养工艺因遗传不稳定、体外培养突变累积及肿瘤细胞残留等会引入额外的风险，体外基因修饰系统的使用也存在病毒载体插入突变、基因编辑工具引发基因重排等隐患。本文基于已有的科学经验及国内外相关指南，围绕药学相关内容对细胞治疗产品的成瘤性致瘤性风险进行讨论，通过对这些潜在风险的剖析，为细胞治疗产品成瘤性、致瘤性控制策略提供参考，助力研究成果快速转化。

Abstract: With the accelerated clinical translation of emerging cellular products, including immune cells and stem cells, their safety risks of tumorigenicity and oncogenicity have attracted much attention. Different types of cell therapy products produced by various manufacturers vary significantly in terms of raw materials, production processes, etc., and corresponding strategies need to be formulated based on the specific risk assessment results. Compared with terminally differentiated somatic cell products, stem cells with multi-directional differentiation have a higher risk of tumorigenicity. Production processes such as culture processes can introduce additional risks due to genetic instability, accumulation of mutations in in vitro culture, and residual tumor cells. The use of in vitro gene modification systems also has hidden dangers, such as insertional mutations of viral vectors and gene rearrangements caused by gene editing tools. Based on existing scientific experience and relevant global guidelines, this paper discusses the tumorigenic and oncogenic risks of cellular products, focusing on chemistry, manufacturing and controls consideration, to provide references for the tumorigenicity and oncogenicity control strategies of cellular products and facilitate the rapid translation of research results.