Lymph-Node Inspired Hydrogels Enhance CAR Expression and Proliferation of CAR T Cells

IF 8.2 2区 材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY ACS Applied Materials & Interfaces Pub Date : 2025-03-05 DOI:10.1021/acsami.4c19942
Miquel Castellote-Borrell, Marc Domingo, Francesca Merlina, Huixia Lu, Salut Colell, Mireia Bachiller, Manel Juan, Sonia Guedan, Jordi Faraudo, Judith Guasch
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Abstract

Chimeric antigen receptor (CAR) T therapy has shown unprecedented results in clinical practice, including long-term complete responses. One of the current challenges of CAR T therapy is to optimize its production in order to lower its cost. Currently, the in vivo activation of T cells by dendritic cells is replicated ex vivo using polymeric magnetic beads coated with antibodies to induce polyclonal T cell activation. However, current practice overlooks the importance of the complex environment that constitutes the lymph nodes, in which T cells activate and proliferate in vivo. Hydrogels are an ideal candidate material for mimicking the properties of natural tissues such as lymph nodes. In this study, key conditions of the composition, stiffness, and microarchitecture of hydrogels were experimentally and theoretically investigated to optimize primary human CAR T cell culture, focusing on CAR expression and proliferation. Poly(ethylene glycol)–heparin hydrogels featuring interconnected pores of 120 μm and an intermediate stiffness of 3.1 kPa were identified as the most suitable conditions for promoting CAR T cell expression and expansion. Specifically, these hydrogels increased the percentage of CAR+ cells by 50% and doubled the replication index compared to suspension cultures. In conclusion, these newly engineered hydrogels are an interesting tool to help improve CAR T cell manufacture and ultimately advance toward a broader clinical implementation of CAR T cell therapy.

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淋巴结激发水凝胶增强CAR - T细胞的表达和增殖
嵌合抗原受体(CAR) T疗法在临床实践中显示出前所未有的结果,包括长期完全缓解。目前CAR - T疗法面临的挑战之一是优化其生产以降低其成本。目前,树突状细胞在体内激活T细胞的方法是在体外利用包被抗体的聚合磁珠诱导多克隆T细胞激活。然而,目前的实践忽视了构成淋巴结的复杂环境的重要性,在这个环境中,T细胞在体内激活和增殖。水凝胶是模拟自然组织(如淋巴结)特性的理想候选材料。本研究对水凝胶的组成、硬度和微结构的关键条件进行了实验和理论研究,以优化原代人CAR - T细胞培养,重点关注CAR的表达和增殖。聚乙二醇-肝素水凝胶的孔间距为120 μm,中间刚度为3.1 kPa,是促进CAR - T细胞表达和扩增的最合适条件。具体来说,与悬浮培养相比,这些水凝胶使CAR+细胞的百分比增加了50%,复制指数增加了一倍。总之,这些新设计的水凝胶是一种有趣的工具,可以帮助改善CAR - T细胞的制造,并最终推动CAR - T细胞治疗在更广泛的临床应用。
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来源期刊
ACS Applied Materials & Interfaces
ACS Applied Materials & Interfaces 工程技术-材料科学:综合
CiteScore
16.00
自引率
6.30%
发文量
4978
审稿时长
1.8 months
期刊介绍: ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.
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