Dou Dehu, Lu Jing, Dou Jinhui, Huo Yan, Gong Xinjiang, Zhang Xuefeng, Chen Xijing
TriApex Laboratories Co., Ltd. Nanjing, Jiangsu, China; China Pharmaceutical University, Nanjing, Jiangsu, China.
TriApex Laboratories Co., Ltd. Nanjing, Jiangsu, China.
Regul Toxicol Pharmacol. 2025 Feb;156:105769. doi: 10.1016/j.yrtph.2024.105769. Epub 2024 Dec 30.
Cell-based therapy, as a "living drug", possesses inherent complexity and heterogeneity. Tumorigenicity evaluation is a crucial aspect of safety assessment for cell-based therapies. Stem cell-based therapies such as hESCs and hiPSCs, may contain residual undifferentiated cells in final product, which have a high potential for proliferation and differentiation, posing a risk of tumor formation in vivo. Additionally, the source, phenotype, differentiation status, proliferative capacity, ex vivo culture conditions, ex vivo processing methods, injection site, and route of administration also influence the tumorigenicity risk of the cells. Tumorigenicity evaluation needs to consider the complexity of design and multifactorial influences. Through the analysis and summary of partial existing marketed and under-development products, combined with practical experience, it is found that there are many differences in requirements and practices related to cell tumorigenicity globally. Regulatory requirements also vary, and guidance and support for applicants' declaration requirements in different regions need to be considered in conjunction with product characteristics and regulatory considerations. This article comprehensively summarizes the requirements of tumorigenicity from main regulatory agencies. Currently, there is no unified global regulatory consensus on technical implementation guide, measures for quantitation or standardization have not been established for evaluation systems. However, based on regulatory requirements and industry practice summaries, through literature research and analysis of tumorigenicity strategy of representative marketed products, the basic focus, and evaluation strategies for tumorigenicity assessment have been preliminarily clarified, providing a reference for the tumorigenicity design of variety of cell-based therapy products.
基于细胞的疗法作为一种“活药物”，具有内在的复杂性和异质性。致瘤性评估是基于细胞疗法安全性评估的关键方面。基于干细胞的疗法，如人胚胎干细胞（hESCs）和诱导多能干细胞（hiPSCs），在最终产品中可能含有残留的未分化细胞，这些细胞具有很高的增殖和分化潜力，在体内有形成肿瘤的风险。此外，细胞的来源、表型、分化状态、增殖能力、体外培养条件、体外处理方法、注射部位和给药途径也会影响细胞的致瘤性风险。致瘤性评估需要考虑设计的复杂性和多因素影响。通过对部分现有已上市和正在研发产品的分析和总结，结合实际经验，发现全球在细胞致瘤性的要求和实践方面存在许多差异。监管要求也各不相同，需要结合产品特点和监管考虑因素，考虑不同地区对申请人申报要求的指导和支持。本文全面总结了主要监管机构对致瘤性的要求。目前，在技术实施指南方面尚无统一的全球监管共识，评估系统的定量方法或标准化措施尚未建立。然而，基于监管要求和行业实践总结，通过文献研究和对代表性已上市产品致瘤性策略的分析，初步明确了致瘤性评估的基本重点和评估策略，为各类基于细胞的治疗产品的致瘤性设计提供参考。
