治疗非霍奇金淋巴瘤的嵌合抗原受体T细胞临床前毒性评价

doi:10.19803/j.1672-8629.2022.08.04

中国药物警戒 ›› 2022, Vol. 19 ›› Issue (8): 828-835.
DOI: 10.19803/j.1672-8629.2022.08.04

• CAR-T 细胞非临床安全性研究与评价专栏 • 上一篇下一篇

治疗非霍奇金淋巴瘤的嵌合抗原受体T细胞临床前毒性评价

文海若¹, 黄瑛^1Δ, 屈哲¹, 姜华¹, 兰洁¹, 楼小燕², 耿兴超¹, 王三龙^1*, 俞磊^2#

¹中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176;
²上海优卡迪生物医药科技有限公司,上海 201203

收稿日期:2022-05-07 出版日期:2022-08-15 发布日期:2022-08-15
通讯作者: ^*王三龙,男,主任药师,药物安全性评价。E-mail：wangsanlong@nifdc.org.cn;^#为共同通信作者。
作者简介:文海若,女,博士,研究员,药物安全性评价。^Δ为并列第一作者。
基金资助:
国家重点研发计划（2021YFA1101602）; 中国科学院战略先导科技专项（XDA1604050202）

Pre-clinical toxicity evaluation of CAR-T cells for the treatment of non-Hodgkin's lymphoma

WEN Hairuo¹, HUANG Ying^1Δ, QU Zhe¹, JIANG Hua¹, LAN Jie¹, LOU Xiaoyan², GENG Xingchao¹, WANG Sanlong^1*, YU Lei^2#

¹National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs, Beijing 100176, China;
²Shanghai Unicar Biomed-Pharmaceutical Technology Co. Ltd., Shanghai 201203, China

Received:2022-05-07 Online:2022-08-15 Published:2022-08-15

摘要/Abstract

摘要： 目的评价治疗非霍奇金淋巴瘤的嵌合抗原受体T（chimeric antigen receptor T, CAR-T）细胞U在荷瘤免疫缺陷小鼠体内的临床前安全性。方法使用NSG小鼠构建Raji-Luc细胞移植瘤模型,并在此基础上单次给予细胞U,持续观察至给药后第8周。考察小鼠体内Raji-Luc细胞荧光强度、小鼠存活率、临床症状、体重变化、血液学指标、淋巴细胞亚群分类、细胞因子指标和组织病理学变化特点。结果细胞U可显著降低体内Raji-Luc细胞荧光强度、抑制荷瘤小鼠体内Raji-Luc细胞增殖,有效缓解Raji-Luc细胞负荷导致的临床表现,一定程度上减缓由Raji-Luc细胞导致的体重降低,延长荷瘤小鼠生存时间,升高荷瘤小鼠血清中人源干扰素（IFN）-γ水平,降低人源白介素（IL）-10水平,升高鼠源肿瘤坏死因子（TNF）和IL-6水平,并明显降低Raji-Luc细胞造模动物各组织器官淋巴瘤发生率,变化呈剂量相关性。细胞U治疗组动物的死因可能与肿瘤的持续性消耗及逐渐加重的背景性病变有关。结论细胞U在Raji-Luc荷瘤NSG小鼠体内未见明显免疫毒性和致瘤性的相关风险,且呈现一定药效学作用。本研究数据可为相关产品非临床安全性评价提供借鉴。

关键词: 嵌合抗原受体T细胞, 非霍奇金淋巴瘤, 免疫缺陷荷瘤小鼠, 毒性评价, 细胞因子, Raji-Luc细胞

Abstract: Objective To evaluate the pre-clinical safety of chimeric antigen receptor T cells named U cells for non-Hodgkin's lymphoma in tumor-bearing immunodeficient mice. Methods The transplanted tumor model of Raji-Luc cells was established in NSG mice, and on this basis, U cells were given at a single dose and the mice were observed continuously until the 8^th week after administration. Then the fluorescence intensity of Raji-Luc cells, survival rate, clinical symptoms, changes of body weight, hematological indexes, classification of lymphocyte subsets, cytokines and histopathological changes in mice were investigated. Results U cells could significantly reduce the fluorescence intensity of Raji-Luc cells in vivo, inhibit the proliferation of Raji-Luc cells, effectively alleviate the clinical manifestations caused by Raji-Luc cells, slow down the weight loss caused by Raji-Luc cells to some extent in tumor-bearing mice, prolong the survival time of tumor-bearing mice, increase the level of human IFN- γ, decrease the level of human IL-10 in serum of tumor-bearing mice, and increase the levels of murine TNF and IL-6, and significantly decrease the production of Raji-Luc cells, which changes in the incidence of lymphoma in various tissues and organs of model animals were dose-related. Conclusion U cells have no obvious immunotoxicity and tumorigenicity risk, and show some pharmacodynamic effects in Raji-Luc NSG mice. Given the above, the data of this study can provide a reference for the non-clinical safety evaluation of related products.

Key words: chimeric antigen receptor T (CAR-T) cells, non-Hodgkin's lymphoma, immunodeficient tumor-bearing mice, toxicity evaluation, cytokines, Raji-Luc Cell

中图分类号:

R979.1

文海若, 黄瑛, 屈哲, 姜华, 兰洁, 楼小燕, 耿兴超, 王三龙, 俞磊. 治疗非霍奇金淋巴瘤的嵌合抗原受体T细胞临床前毒性评价[J]. 中国药物警戒, 2022, 19(8): 828-835.

WEN Hairuo, HUANG Ying, QU Zhe, JIANG Hua, LAN Jie, LOU Xiaoyan, GENG Xingchao, WANG Sanlong, YU Lei. Pre-clinical toxicity evaluation of CAR-T cells for the treatment of non-Hodgkin's lymphoma[J]. Chinese Journal of Pharmacovigilance, 2022, 19(8): 828-835.

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治疗非霍奇金淋巴瘤的嵌合抗原受体T细胞临床前毒性评价

Pre-clinical toxicity evaluation of CAR-T cells for the treatment of non-Hodgkin's lymphoma

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