N. A. Goryacheva, Dmitrij Ivanovic Rzhevskiy, Gulsara Amsngalievna Slashheva, N. I. Novikova, Mikhail Valentinivich Kisilevskiy, I. Chikileva, Rajmonda Yanovna Vlasenko, I. A. Dyachenko, A. N. Murashev, Dmitrij Aleksandrovich Bondarenko
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引用次数: 0
Abstract
Introduction. The Car-T-cell therapy is current and modern promising method for the oncology treatment. USA Food and Drug Sanitary Control Department confirms six drugs for cellular immunotherapy the blood oncology today. But the information about biomedical product preclinical test is absent, because used T-cells (cell with chimeric antigen receptor) are autologous for humans, which is the problem for use classic toxicity tests. Besides the biomedical product safety becomes questionable, therefore the different preclinical research strategy is developed to solve those problems and produce normal test-systems with therapeutic target. The aim of the study was to evaluate the acute toxicity in immunodeficient BALB/c Nude mice of an antineoplastic drug based on genetically modified T/NK cells that express a chimeric T-cell anti-HER2 receptor. Material and methods. Test and control groups consisted of five males and five females. Animals were injected a single intravenous or intraperitoneal injection of the testing product and the solvent-cryopreserving carrier at the dose 0,2 ml/animal. There were two doses: equal to the human therapeutic 0,5•106 cell/animal dose and ten times over then the therapeutic dose 5•106 cell/animal. During the test the animal’s weight, the food intake and clinically symptoms of the testing product toxicity were registered. On the fifteenth of the study day animals were euthanatized and exposed to a necropsy with the organs’ macroscopic inspection, the weighting and fixating. The detection of the testing biomedical product toxicity was the aim of the histology analysis. Results. A single intravenous or intraperitoneal injection of the biomedical product «anti-HER2-CAR-T/ CAR-NK» at the human therapeutic dose, as well as in 10 times more than the same, is safe for BALB/c Nude mice. The preclinical study has shown the absence of significant toxic effects. Limitations. The research was performed on Balb/c nude line immunodeficient mice, because the tested product contained living foreign cells. Conclusion. This work can be the main basis for the creation of biomedical product preclinical research protocol of biomedical cell products produced from CAR-technology.
CAR技术产品用于恶性肿瘤治疗的临床前急性毒性研究,以“抗her2 -CAR- t /CAR- nk”为例
介绍。car - t细胞疗法是目前最具发展前景的肿瘤治疗方法。美国食品和药物卫生控制部门今天确认了六种用于细胞免疫治疗血液肿瘤的药物。但由于使用的t细胞(嵌合抗原受体细胞)对人体来说是自体的,这是传统的毒性试验存在的问题,因此缺乏生物医学产品临床前试验的相关信息。此外,生物医药产品的安全性也受到质疑,因此,人们制定了不同的临床前研究策略来解决这些问题,并生产出具有治疗目标的正常试验系统。该研究的目的是评估一种基于表达嵌合T细胞抗her2受体的转基因T/NK细胞的抗肿瘤药物对免疫缺陷BALB/c裸鼠的急性毒性。材料和方法。实验组和对照组分别为5名男性和5名女性。动物单次静脉或腹腔注射试验品和溶剂-低温保存载体,剂量为0.2 ml/只。有两种剂量:等于人类治疗剂量0,5•106细胞/动物和10倍以上的治疗剂量5•106细胞/动物。试验期间记录动物体重、摄食量和试验产品毒性的临床症状。在研究当天的第15天,对动物实施安乐死,并进行尸检,对器官进行肉眼检查,称重和固定。组织学分析的目的是检测被试生物制品的毒性。结果。单次静脉或腹腔注射人体治疗剂量的生物医学产品“抗her2 - car - t / CAR-NK”,以及10倍以上的剂量,对BALB/c裸鼠是安全的。临床前研究显示没有明显的毒性作用。的局限性。本研究是在Balb/c裸系免疫缺陷小鼠身上进行的,因为被测产品含有活的外源细胞。结论。本工作可为car技术生产的生物医学细胞产品临床前研究方案的制定提供主要依据。