抗CD19嵌合抗原受体T细胞IM19的临床前及临床安全性研究  

Pre-clinical and clinical studies of the safety profiles of IM19 CAR-T cells

作　　者：应志涛[1] 宋玉琴[1] 王小沛[1] 郑文[1] 林宁晶[1] 涂梅峰[1] 谢彦[1] 平凌燕 张晨[1] 刘卫平[1] 邓丽娟[1] 鲁薪安 何霆 齐菲菲 胡雪莲 朱军[1] YING Zhi-tao;SONG Yu-qin;WANG Xiao-pei;ZHENG Wen;LIN Ning-jing;TU Mei-feng;XIE Yan;PING Ling-yan;ZHANG Chen;LIU Wei-ping;DENG Li-juan;LU Xin-an;HE Ting;Qi Fei-fei;HU Xue-lian;ZHU Jun(Department of Lymphoma , Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142;Beijing Immunochina Pharmaceuticals,Co.,Ltd.,Beijing 100195,China)

机构地区：[1]北京大学肿瘤医院暨北京市肿瘤防治研究所淋巴瘤科恶性肿瘤发病机制及转化研究教育部重点实验室,北京100142 [2]北京艺妙神州医药科技有限公司,北京100195

出　　处：《中国新药杂志》2019年第6期697-702,共6页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(81600164);北京市自然科学基金资助项目(7172046);北京市属医院科研培育计划资助项目(PX2017001)

摘　　要：目的:在临床前及临床研究中探讨抗CD19嵌合抗原受体T细胞IM19的安全性。方法:通过静脉血管刺激(新西兰兔)、过敏(豚鼠)和溶血实验检测IM19试剂的安全性;通过急性毒性和成瘤性检查(小鼠)分析IM19对机体的毒性;通过基因测序检测方法分析IM19潜在的致癌性。入组复发难治B细胞淋巴瘤患者接受IM19 CAR-T细胞治疗,观察其安全性数据。结果:IM19对新西兰兔局部注射没有刺激;未使豚鼠产生过敏反应;溶血结果为阴性。IM19对实验动物安全,未见明显毒性,未见潜在的致癌性和成瘤性。3例复发难治B细胞淋巴瘤患者接受IM19 CAR T细胞治疗,无患者发生严重的细胞因子释放综合征或神经毒性,患者仅接受对症支持治疗。结论:临床前及临床研究结果显示,IM19 CAR-T细胞具有较好的安全性,值得进一步扩大临床研究。Objective : To investigate the safety profiles of IM 19 CAR-T cells in pre-clinical and clinical studies. Methods: The safety of CAR-T cell injection was detected by intravenous vascular stimulation ( New Zealand rabbits), allergy ( Guinea pig) and hemolysis tests. In vivo study was conducted to evaluate the oncogenesis of IM 19 CAR-T cells in NOD-SCID mice. A genomic insertion site analyzed the carcinogenicity of IM 19 CAR-T cells. A clinical trial was initiated to study the safety of IM 19 CAR-T cells in relapsed or refractory B cell lymphomas. Results: There was no histologic evidence of local toxicity associated with IM 19 versus normal saline. IM 19 CAR-T cells did not cause allergy and lysis of rabbit RBC. There was no carcinogenicity and tumorigenesis associated with IM 19 CAR-T cells. Three patients with relapsed or refractory B cell lymphomas were enrolled in the clinical trial, and received IM 19 CAR-T cell infusion. No patients experienced sever cytokine release syndrome or neurotoxicities. Conclusion: The pre-clinical and clinical studies demonstrate that IM 19 CAR-T cells are safe and need to be investigated in a larger patient cohort.

关 键 词：嵌合抗原受体T细胞 细胞因子释放综合征 神经毒性 细胞因子 不良反应 

分 类 号：R979.1[医药卫生—药品]