诱导多能干细胞衍生的工程化 T 细胞:从研究到临床应用。
Engineered T cells from induced pluripotent stem cells: from research towards clinical implementation.
机构信息
Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, Netherlands.
出版信息
Front Immunol. 2024 Jan 12;14:1325209. doi: 10.3389/fimmu.2023.1325209. eCollection 2023.
Induced pluripotent stem cell (iPSC)-derived T (iT) cells represent a groundbreaking frontier in adoptive cell therapies with engineered T cells, poised to overcome pivotal limitations associated with conventional manufacturing methods. iPSCs offer an off-the-shelf source of therapeutic T cells with the potential for infinite expansion and straightforward genetic manipulation to ensure hypo-immunogenicity and introduce specific therapeutic functions, such as antigen specificity through a chimeric antigen receptor (CAR). Importantly, genetic engineering of iPSC offers the benefit of generating fully modified clonal lines that are amenable to rigorous safety assessments. Critical to harnessing the potential of iT cells is the development of a robust and clinically compatible production process. Current protocols for genetic engineering as well as differentiation protocols designed to mirror human hematopoiesis and T cell development, vary in efficiency and often contain non-compliant components, thereby rendering them unsuitable for clinical implementation. This comprehensive review centers on the remarkable progress made over the last decade in generating functional engineered T cells from iPSCs. Emphasis is placed on alignment with good manufacturing practice (GMP) standards, scalability, safety measures and quality controls, which constitute the fundamental prerequisites for clinical application. In conclusion, the focus on iPSC as a source promises standardized, scalable, clinically relevant, and potentially safer production of engineered T cells. This groundbreaking approach holds the potential to extend hope to a broader spectrum of patients and diseases, leading in a new era in adoptive T cell therapy.
诱导多能干细胞(iPSC)衍生的 T(iT)细胞代表了基因工程 T 细胞过继细胞疗法的一个开创性前沿领域,有望克服传统制造方法相关的关键限制。iPSC 提供了治疗性 T 细胞的现货来源,具有无限扩增和简单遗传操作的潜力,以确保低免疫原性,并引入特定的治疗功能,如通过嵌合抗原受体(CAR)实现抗原特异性。重要的是,iPSC 的基因工程具有生成完全修饰的克隆系的优势,这些克隆系适合进行严格的安全性评估。利用 iT 细胞的潜力的关键是开发一种强大且临床兼容的生产工艺。目前的基因工程和旨在模拟人类造血和 T 细胞发育的分化方案在效率上存在差异,并且常常包含不合规的成分,因此不适合临床实施。本综述集中讨论了过去十年中在从 iPSC 生成功能性基因工程 T 细胞方面取得的显著进展。重点放在符合良好生产规范(GMP)标准、可扩展性、安全性措施和质量控制上,这些是临床应用的基本前提。总之,关注 iPSC 作为来源有望实现标准化、可扩展、临床相关且潜在更安全的基因工程 T 细胞生产。这种开创性的方法有可能将希望扩展到更广泛的患者和疾病群体,引领过继 T 细胞治疗的新时代。