异体CD19嵌合抗原受体双阴性T细胞作为现成的免疫治疗药物治疗b细胞恶性肿瘤的临床前研究。

IF 4.6 2区 医学 Q2 IMMUNOLOGY
Dan Wang, Liuyang Wang, Shuai Liu, Jianjun Tong, Honglin Zhu, Man Xu, Xiancai Li, Zhiqiang Xiang, Qinghua Sun, Hengcai Wang, Yuli Wang, Shuyang Wang, Liming Yang
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引用次数: 0

摘要

目的:评价同种异体CD19嵌合抗原受体双阴性T细胞(CD19- car - dnts)作为一种现成的治疗细胞产品的可制造性、有效性和安全性。方法:采用膜蛋白质组阵列检测CD19-CAR的脱靶结合。用编码CD19-CAR的慢病毒载体转导来自健康供体的dnt。在GMP条件下制备CD19-CAR-DNTs,并使用流式细胞术表征其表面分子表达模式。我们通过在体外评估冷冻保存的CD19- car - dnts的细胞活力以及它们对各种CD19+靶细胞系和原代患者细胞的细胞毒性,研究了CD19- car - dnts的现成潜力。我们评估了冷冻保存的CD19-CAR-DNTs在体内异种移植模型中的持久性和安全性。结果:制备出gmp级CD19-CAR-DNTs并冷冻保存。冷冻保存的CD19- car - dnts对各种CD19+靶细胞系和原代患者原细胞保持活性和抗肿瘤活性。这些细胞显著延长了raji - luc异种移植NOG小鼠的存活时间。多次输注细胞可进一步增强其功效。值得注意的是,在小鼠体内单次输注后,CD19-CAR-DNTs最初迅速分布在灌注良好的器官中,并逐渐扩散到大多数组织,在第43天达到峰值。在毒性研究中,CD19-CAR-DNTs显著减轻了荷瘤NOG小鼠的肿瘤负荷并改善了组织损伤。关键的是,在非荷瘤NOG小鼠中没有观察到免疫毒性或移植物抗宿主病。结论:同种异体CD19-CAR-DNTs满足了一种现成的治疗细胞产品的要求,为治疗血液系统恶性肿瘤提供了一种有希望的新方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A preclinical study of allogeneic CD19 chimeric antigen receptor double-negative T cells as an off-the-shelf immunotherapy drug against B-cell malignancies

A preclinical study of allogeneic CD19 chimeric antigen receptor double-negative T cells as an off-the-shelf immunotherapy drug against B-cell malignancies

Objectives

To evaluate the manufacturability, efficacy and safety of allogeneic CD19 chimeric antigen receptor double-negative T cells (CD19-CAR-DNTs) as an off-the-shelf therapeutic cell product.

Methods

A membrane proteome array was used to assess the off-target binding of CD19-CAR. DNTs derived from healthy donors were transduced with lentiviral vectors encoding the CD19-CAR. The manufacture of the CD19-CAR-DNTs was under GMP conditions, and their surface molecule expression patterns were characterised using flow cytometry. We investigated the off-the-shelf potential of CD19-CAR-DNTs by evaluating the cryopreserved CD19-CAR-DNTs in terms of cell viability as well as their cytotoxicity against various CD19+ target cell lines and primary patient blasts in vitro. We evaluated the persistence and safety of the cryopreserved CD19-CAR-DNTs in xenograft models in vivo.

Results

GMP-grade CD19-CAR-DNTs were manufactured and cryopreserved for use in advance. The cryopreserved CD19-CAR-DNTs maintain their viability and antitumor activity against various CD19+ target cell lines and primary patient blasts. These cells significantly prolonged the survival in Raji-Luc-xenografted NOG mice. Multiple infusions of the cells can further augment their efficacy. Remarkably, following a single infusion in mice, CD19-CAR-DNTs rapidly got distributed among well-perfused organs initially, and progressively spread to most tissues, peaking at Day 43. In toxicity studies, CD19-CAR-DNTs significantly reduced tumor burden and ameliorated tissue damage in tumor-bearing NOG mice. Critically, no immunotoxicity or graft versus host disease was observed in non-tumor-bearing NOG mice.

Conclusions

The allogeneic CD19-CAR-DNTs fulfil the requirements of an off-the-shelf therapeutic cell product, offering a promising new approach to the treatment of haematological malignancies.

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来源期刊
Clinical & Translational Immunology
Clinical & Translational Immunology Medicine-Immunology and Allergy
CiteScore
12.00
自引率
1.70%
发文量
77
审稿时长
13 weeks
期刊介绍: Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.
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