Huang Baozhu, Luo Liqun, Wang Jun, He Bailin, Feng Rui, Xian Na, Zhang Qiong, Chen Lieping, Huang Gangxiong
Laboratory of Immunotherapy, Sun Yat-sen University, Guangzhou, China.
Institute of Immunotherapy, Fujian Medical University, Fuzhou, China.
Oncoimmunology. 2019 Nov 4;9(1):1684127. doi: 10.1080/2162402X.2019.1684127. eCollection 2020.
The application of chimeric antigen receptor (CAR)-T cell therapy in patients with advanced solid tumors remains a significant challenge. Simultaneously targeting antigen and the solid tumor microenvironment are two major factors that greatly impact CAR-T cell therapy outcomes. In this study, we engineered CAR-T cells to specifically target B7-H3, a protein commonly found in solid human tumors, using a single-chain variable fragment (scFv) derived from an anti-B7-H3 monoclonal antibody. We tested the antitumor activity of B7-H3 CAR-T cells in mouse models with solid human tumors and determined that B7-H3 CAR-T cells exhibited potent antitumor activity against B7-H3 tumor cells and . In addition, PD-1 decoy receptors were engineered to include extracellular PD-1 fused to the intracellular stimulatory domain of either CD28 or IL-7 receptor, respectively, which were then introduced into B7-H3 CAR-T cells. As a result, these newly modified, superior CAR-T cells exhibited more persistent antitumor activity in B7-H3/B7-H1 tumors . Our findings indicate that B7-H3 specific CAR-T cells have the potential to treat multiple types of advanced solid tumors.
嵌合抗原受体（CAR）-T细胞疗法在晚期实体瘤患者中的应用仍然是一项重大挑战。同时靶向抗原和实体瘤微环境是极大影响CAR-T细胞治疗结果的两个主要因素。在本研究中，我们使用源自抗B7-H3单克隆抗体的单链可变片段（scFv），设计工程化CAR-T细胞以特异性靶向B7-H3，这是一种在人类实体瘤中常见的蛋白质。我们在携带人类实体瘤的小鼠模型中测试了B7-H3 CAR-T细胞的抗肿瘤活性，确定B7-H3 CAR-T细胞对B7-H3肿瘤细胞表现出强大的抗肿瘤活性。此外，PD-1诱饵受体被设计为分别包含与CD28或IL-7受体的细胞内刺激结构域融合的细胞外PD-1，然后将其引入B7-H3 CAR-T细胞。结果，这些新修饰的、更优的CAR-T细胞在B7-H3/B7-H1肿瘤中表现出更持久的抗肿瘤活性。我们的研究结果表明，B7-H3特异性CAR-T细胞有潜力治疗多种类型的晚期实体瘤。
