Preclinical Evaluation of Chimeric Antigen Receptor–Modified T Cells Specific to Epithelial Cell Adhesion Molecule for Treating Colorectal Cancer
Preclinical Evaluation of Chimeric Antigen Receptor–Modified T Cells Specific to Epithelial Cell Adhesion Molecule for Treating Colorectal Cancer
复制标题
上皮细胞粘附分子特异性嵌合抗原受体修饰 T 细胞治疗结直肠癌的临床前评估
DOI：
10.1089/hum.2018.229
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发表时间：
2019
影响因子：
4.2
通讯作者：
Wang Wei
中科院分区：
文献类型：
--
作者：
Zhang Bing-Lan;Li Dan;Gong You-Ling;Huang Yong;Qin Di-Yuan;Jiang Lin;Liang Xiao;Yang Xiao;Gou Hong-Feng;Wang Yong-Sheng;Wei Yu-Quan;Wang Wei
嵌合抗原受体修饰 T 细胞（CAR-T 细胞）已成为一种有前途的实体瘤癌症免疫疗法。上皮细胞粘附分子 (EpCAM) 在多种肿瘤中过度表达，被认为是循环肿瘤细胞和癌症干细胞的生物标志物，是过继性 T 细胞免疫治疗的一个有吸引力的靶标。本研究通过慢病毒载体生成了对 EpCAM 具有重定向特异性的第三代 CAR-T 细胞（EpCAM CAR-T）。研究表明，EpCAM CAR-T细胞可以以EpCAM依赖性方式对靶细胞引发裂解性细胞毒性，并分泌细胞毒性细胞因子，包括干扰素γ和肿瘤坏死因子α。此外，EpCAM CAR-T 细胞的过继转移显着延迟了异种移植模型中肿瘤的生长和形成。此外，安全性评价表明，CAR-T细胞在小鼠体内无全身毒性。该数据证实了靶向EpCAM的CAR-T细胞的抗肿瘤能力和安全性，可能为CAR-T细胞疗法治疗实体瘤提供新的靶点。
Chimeric antigen receptor–modified T cells (CAR-T cells) have emerged as a promising cancer immunotherapy for solid tumors. Epithelial cell adhesion molecule (EpCAM) is overexpressed in a variety of tumors and is recognized as a biomarker for circulating tumor cells and cancer stem cells, representing an attractive target for adoptive T-cell immunotherapy. This study generated third-generation CAR-T cells with redirected specificity to EpCAM (EpCAM CAR-T) by lentiviral vector. The study demonstrated that EpCAM CAR-T cells can elicit lytic cytotoxicity to target cells in an EpCAM-dependent manner and secrete cytotoxic cytokines, including interferon gamma and tumor necrosis factor alpha. Furthermore, adoptive transfer of EpCAM CAR-T cells significantly delayed tumor growth and formation in xenograft models. In addition, the safety evaluation showed that CAR-T cells have no systemic toxicity in mice. The data confirmed the antitumor ability and safety of CAR-T cells targeting EpCAM and may provide a new target for CAR-T cell therapies in treating solid tumors.