Zhang Weiguang, Wang Chunling, Tao Zhibo, Yin Changlin, Gao Jimin
Department of Critical Care Medicine, Southwest Hospital, Chongqing 400038, China.
School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
Sheng Wu Gong Cheng Xue Bao. 2020 Oct 25;36(10):2162-2170. doi: 10.13345/j.cjb.200374.
We constructed the CS1-targeted second- and third-generation CAR-T cells with genetic engineered 4-1BB or/and ICOS as a costimulatory signaling molecule by use of lentiviral platform. The CS1-targeted second-generation CAR-T cells with ICOS or 4-1BB had similar anti-neoplastic activity. When effector/target ratio was 1:1, the CAR-T cells with ICOS showed better killing effect on IM9-lucgfp cells than those with 4-1BB. However, The CS1-targeted third-generation CAR-T cells exihibited lower cytolytic capacity against IM9-lucgfp cells than the CS1-targeted second-generation CAR-T cells when the ratio of effector/target was 1:1, 2:1 or 5:1. When the ratio of effector/target was 10:1, the killing efficacy of both the second- and third-generation CAR-T cells against IM9-lucgfp cells was more than 85%, significantly higher than that of the control T cells. Taken together, both the CS1-targeted second- and third-generation CAR-T cells with ICOS or/and 4-1BB could efficiently kill CS1-positive multiple myeloma cells, but the CS1-targeted second-generation CAR-T cells had more potent killing effect on CS1-positive multiple myeloma cells than the CS1-targeted third-generation CAR-T cells.
我们利用慢病毒平台构建了以CS1为靶点的第二代和第三代嵌合抗原受体T细胞（CAR-T细胞），其共刺激信号分子采用基因工程改造的4-1BB或/和诱导性共刺激分子（ICOS）。携带ICOS或4-1BB的以CS1为靶点的第二代CAR-T细胞具有相似的抗肿瘤活性。当效应细胞/靶细胞比例为1:1时，携带ICOS的CAR-T细胞对IM9-lucgfp细胞的杀伤效果优于携带4-1BB的CAR-T细胞。然而，当效应细胞/靶细胞比例为1:1、2:1或5:1时，以CS1为靶点的第三代CAR-T细胞对IM9-lucgfp细胞的细胞溶解能力低于以CS1为靶点的第二代CAR-T细胞。当效应细胞/靶细胞比例为10:1时，第二代和第三代CAR-T细胞对IM9-lucgfp细胞的杀伤效率均超过85%，显著高于对照T细胞。综上所述，携带ICOS或/和4-1BB的以CS1为靶点的第二代和第三代CAR-T细胞均可有效杀伤CS1阳性的多发性骨髓瘤细胞，但以CS1为靶点的第二代CAR-T细胞对CS1阳性的多发性骨髓瘤细胞的杀伤作用比以CS1为靶点的第三代CAR-T细胞更强。
