纳米体衍生的双特异性CAR-T细胞疗法增强了T细胞淋巴瘤治疗的抗肿瘤疗效。

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy Oncolytics Pub Date : 2023-09-21 DOI:10.1016/j.omto.2023.07.007
Baijin Xia, Keming Lin, Xuemei Wang, FeiLi Chen, Mo Zhou, Yuzhuang Li, Yingtong Lin, Yidan Qiao, Rong Li, Wanying Zhang, Xin He, Fan Zou, Linghua Li, Lijuan Lu, Cancan Chen, WenYu Li, Hui Zhang, Bingfeng Liu
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引用次数: 1

摘要

T细胞淋巴瘤(TCL)是一种高度异质性的疾病,预后差,5年总生存率低。目前的治疗方案的有效率相对较低。单靶点嵌合抗原受体T细胞(CAR-T细胞)治疗T淋巴细胞的临床研究需要大量和多次输注,增加了治疗的风险和成本;因此,优化靶向治疗是改善整体预后的途径之一。尽管双特异性CAR-T细胞疗法在治疗B细胞淋巴瘤中避免抗原逃逸方面取得了重大进展,但将该策略应用于TCL仍需进一步研究。在此,我们构建了羊驼纳米体噬菌体文库,并分别生成了靶向CD30和CD5的高亲和力和特异性Nbs。在多轮筛选的基础上,构建了双特异性NbCD30-CD5-CAR - T细胞,并在体外和体内验证了其对TCL的优越抗肿瘤作用。我们的研究结果表明,与单靶点CAR-T细胞和双特异性单链可变片段(scFv)衍生的CAR-T细胞相比,nb衍生的双特异性CAR-T细胞在TCL治疗中的抗肿瘤疗效显著提高。由于Nbs更小,免疫原性更低,基于nb的双特异性CAR-T细胞的协同作用可能会提高其在未来临床应用中的安全性和有效性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Nanobody-derived bispecific CAR-T cell therapy enhances the anti-tumor efficacy of T cell lymphoma treatment.

T cell lymphoma (TCL) is a highly heterogeneous group of diseases with a poor prognosis and low 5-year overall survival rate. The current therapeutic regimens have relatively low efficacy rates. Clinical studies of single-target chimeric antigen receptor T cell (CAR-T cell) therapy in T lymphocytes require large and multiple infusions, increasing the risks and cost of treatment; therefore, optimizing targeted therapy is a way to improve overall prognosis. Despite significant advances in bispecific CAR-T cell therapy to avoid antigen escape in treatment of B cell lymphoma, applying this strategy to TCL requires further investigation. Here, we constructed an alpaca nanobody (Nb) phage library and generated high-affinity and -specificity Nbs targeting CD30 and CD5, respectively. Based on multiple rounds of screening, bispecific NbCD30-CD5-CAR T cells were constructed, and their superior anti-tumor effect against TCL was validated in vitro and in vivo. Our findings demonstrated that Nb-derived bispecific CAR-T cells significantly improved anti-tumor efficacy in TCL treatment compared with single-target CAR-T cells and bispecific single chain variable fragment (scFv)-derived CAR-T cells. Because Nbs are smaller and less immunogenic, the synergistic effect of Nb-based bispecific CAR-T cells may improve their safety and efficacy in future clinical applications.

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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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