Liu Zeyang, Li Yan-Ruide, Yang Youcheng, Zhu Yu, Yuan Weihao, Hoffman Tyler, Wu Yifan, Zhu Enbo, Zarubova Jana, Shen Jun, Nan Haochen, Yeh Kun-Wei, Hasani-Sadrabadi Mohammad Mahdi, Zhu Yichen, Fang Ying, Ge Xinyang, Li Zhizhong, Soto Jennifer, Hsiai Tzung, Yang Lili, Li Song
Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Biomed Eng. 2024 Dec;8(12):1615-1633. doi: 10.1038/s41551-024-01272-w. Epub 2024 Oct 25.
The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8 T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy.
使用合成抗原呈递细胞来激活和扩增工程化T细胞以治疗癌症,通常会导致疗效和持久性欠佳的疗法。在此,我们描述了一种高通量微流控系统,用于制造模拟抗原呈递细胞的粘弹性和T细胞激活特性的合成细胞。与刚性或弹性微球相比,合成粘弹性T细胞激活细胞(SynVACs)显著增强了人类CD8 T细胞的扩增,并抑制了调节性T细胞的形成。值得注意的是,用SynVACs激活和扩增嵌合抗原受体(CAR)T细胞,可使CAR转导效率达到约90%,并使T记忆干细胞大幅增加。工程化CAR T细胞在人淋巴瘤小鼠模型中消除了肿瘤细胞,抑制了人卵巢癌异种移植小鼠的肿瘤生长,持续时间更长,并降低了肿瘤复发风险。我们的研究结果强调了粘弹性在T细胞工程中的关键作用,并突出了SynVACs在癌症治疗中的效用。
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