摘要
目的评价2种靶向CD19的嵌合抗原受体基因修饰的T(chimeric antigen receptor gene modified T,CAR-T)细胞在荷瘤免疫缺陷小鼠体内的药效,为相关产品的体内药效学评价提供参考。方法使用B-NDG小鼠构建经萤火虫荧光素酶标记的Raji细胞(Raji-Luc细胞)移植瘤模型,单次给予细胞A和细胞B(相对于细胞A,细胞B在表达CAR结构的基础上还表达IL-6沉默片段,可干扰IL-6的表达),持续观察至给药后84 d。考察小鼠存活率、临床症状、体重变化、体内Raji-Luc细胞荧光强度和组织病理学变化特点。结果细胞A和细胞B均可明显延长荷瘤小鼠生存时间,并一定程度上减缓由Raji-Luc细胞导致的体重降低,有效缓解Raji-Luc细胞负荷导致的临床表现,显著降低体内Raji-luc细胞荧光强度,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。结论CAR-T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。细胞A和细胞B在Raji-Luc细胞荷瘤B-NDG小鼠体内呈现一定药效学作用,两者药效未见明显差异。
Objective To evaluate the efficacy of two CD19-targeting chimeric antigen receptor gene modified T cells(CAR-T)in tumor-bearing immunodeficient mice so as to provide a reference for the in vivo pharmacodynamics evaluation of related products.Methods Firefly luciferase-labeled Raji cell(Raji-Luc)xenograft model was established in B-NDG mice,and both cell A and cell B(compared with cell A,on the basis of expressing the CAR structure,cell B express the IL-6 silencer fragment to interfere with the expression of IL-6)were administered for single time on this basis,and continuedly observed until 84 days after administration.The survival rate,clinical symptoms,body weight changes,fluorescence intensity of Raji-Luc cells in vivo and histopathological changes of mice were investigated.Results Both cell A and cell B could significantly prolong the survival time of tumor-bearing mice,slow down the weight loss caused by Raji-Luc cells to a certain extent,effectively alleviate the clinical manifestations caused by the loading of Raji-Luc cells,and significantly reduce Raji-luc in vivo.The fluorescence intensity of cells significantly reduced the incidence of lymphoma in various tissues and organs of Raji-Luc cell model animals,and the changes were dose-related.Conclusion The cause of death of animals in the CAR-T treatment group may be related to the continuous consumption of the tumor and the progressively worsening background lesions.Both cell A and cell B showed a certain pharmacodynamic effect in Raji-Luc tumor-bearing B-NDG mice,and there was no significant difference in the pharmacodynamics.
作者
文海若
黄瑛
屈哲
秦超
王三龙
楼小燕
耿兴超
俞磊
WEN Hairuo;HUANG Ying;QU Zhe;QIN Chao;WANG Sanlong;LOU Xiaoyan;GENG Xingchao;YU Lei(National 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;Shanghai Unicar Biomed-Pharmaceutical Technology Co.Ltd.,Shanghai 201203,China)
出处
《中国药物警戒》
2022年第8期817-822,共6页
Chinese Journal of Pharmacovigilance
基金
国家重点研发计划(2021YFA1101602)
中国科学院战略先导科技专项(XDA1604050202)。
