电容技术实现了CAR-T细胞搅拌罐生物反应器培养物的自动进料、改进的扩增和更高的通量

摘要(中文译文)

嵌合抗原受体（CAR）T细胞为治疗某些血液系统恶性肿瘤提供了一种新颖且具有变革性的方法。然而，CAR-T细胞的扩增方法仍处于开发阶段，且往往依赖于人工、低控制度的培养方式。向生物反应器的过渡将实现更高的过程控制水平和可扩展性，是该领域研究的重点方向。尽管如此，目前仍缺乏无需人工细胞取样即可判断培养进程的方法，而人工取样存在引入误差和增加污染风险的问题。本文中，我们通过比较T细胞和CAR-T细胞生物工艺与广泛用于生物技术领域且已有成熟电容应用的中国仓鼠卵巢（CHO）培养，评估了电容技术能否提供可靠的在线细胞浓度测定。在发现电容技术能够准确测量CAR-T细胞浓度后，我们进一步展示了利用电容衍生触发信号实现自动化补料的可行性，该方式在细胞浓度和通量方面改善了生物工艺性能。我们预期本研究将拓展以电容作为合适的过程分析技术（PAT）来实现CAR-T细胞制造——乃至其他细胞与基因治疗产品——监测与控制的探索途径。该技术还可能实现多批次的远程监测、收获控制以及为建模生成大量过程数据，从而进一步推动该领域的发展。

Abstract

Chimeric antigen receptor (CAR) T cells present a novel and transformative approach to treat certain haematological malignancies. However, CAR-T cell expansion methods are still under development and often rely on manual, low-control culture methods. The transition to bioreactors would allow for greater process control and scalability and is a key focus of research in the field. Despite this, there are few methods to determine culture progression without the need for manual cell sampling which risks introducing errors and heightening contamination risks. In this article, we assessed whether capacitance technology could deliver reliable, on-line cell concentrations by comparing T cell, and CAR-T cell bioprocesses with Chinese hamster ovary (CHO) cultures-widely used in biotechnology and with established capacitance usage. Finding that capacitance technology could accurately measure CAR-T cell concentrations, we then demonstrated the automation of feeding using capacitance-derived triggers which improved bioprocess performance in terms of cell concentration and throughput. We anticipate that this study will expand avenues of investigation regarding capacitance as a suitable process analytical technology (PAT) to enable monitoring and control of CAR-T cell manufacture, and potentially other cell and gene therapy products. It may also enable remote monitoring of multiple batches, harvest control, and the generation of large collections of process data for modelling, which will further progress the field.

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