UCL Cancer Institute, University College London, London, UK.
Royal Free Hospital London, NHS Foundation Trust, London, UK.
Adv Exp Med Biol. 2023;1420:117-137. doi: 10.1007/978-3-031-30040-0_8.
Chimeric antigen receptor (CAR) T-cells are considered "living drugs" and offer a compelling alternative to conventional anticancer therapies. Briefly, T-cells are redirected, using gene engineering technology, toward a specific cancer cell surface target antigen via a synthetic chimeric antigen receptor (CAR) protein. CARs have a modular design comprising four main structures: an antigen-binding domain, a hinge region, a transmembrane domain, and one or more intracellular signaling domains for T-cell activation. A major challenge in the CAR T-cell manufacturing field is balancing product quality with scalability and cost-effectiveness, especially when transitioning from an academic clinical trial into a marketed product, to be implemented across many collection, manufacturing, and treatment sites. Achieving product consistency while circumnavigating the intrinsic variability associated with autologous products is an additional barrier. To overcome these limitations, a robust understanding of the product and its biological actions is crucial to establish a target product profile with a defined list of critical quality attributes to be assessed for each batch prior to product certification. Additional challenges arise as the field progresses, such as new safety considerations associated with the use of allogenic T-cells and genome editing tools. In this chapter, we will discuss the release and potency assays required for CAR T-cell manufacturing, covering their relevance, current challenges, and future perspectives.
嵌合抗原受体 (CAR) T 细胞被认为是“活的药物”，为传统抗癌疗法提供了一种极具吸引力的替代方案。简而言之，T 细胞通过基因工程技术被重定向，通过一种合成的嵌合抗原受体 (CAR) 蛋白针对特定的癌细胞表面靶抗原。CAR 具有模块化设计，包括四个主要结构：抗原结合结构域、铰链区、跨膜结构域和一个或多个用于 T 细胞激活的细胞内信号转导结构域。在 CAR T 细胞制造领域的一个主要挑战是在产品质量、可扩展性和成本效益之间取得平衡，特别是在从学术临床试验过渡到商业化产品并在许多采集、制造和治疗场所实施时。在规避与自体产品相关的固有变异性的同时实现产品一致性是另一个障碍。为了克服这些限制，必须深入了解产品及其生物学作用，以建立具有目标产品概况的产品，其中列出了在产品认证之前要评估的每个批次的关键质量属性。随着该领域的进展，还会出现其他挑战，例如与使用同种异体 T 细胞和基因组编辑工具相关的新的安全考虑因素。在本章中，我们将讨论 CAR T 细胞制造所需的放行和效力检测，涵盖其相关性、当前挑战和未来展望。
