Zhou Linfu, Li Yao, Zheng Diwei, Zheng Yongfang, Cui Yuanbin, Qin Le, Tang Zhaoyang, Peng Dongdong, Wu Qiting, Long Youguo, Yao Yao, Wong Nathalie, Lau James, Li Peng
China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, the CUHK-GIBH Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Mol Ther Oncol. 2024 May 23;32(2):200817. doi: 10.1016/j.omton.2024.200817. eCollection 2024 Jun 20.
Chimeric antigen receptor (CAR) T cell therapy has demonstrated robust efficacy against hematological malignancies, but there are still some challenges regarding treating solid tumors, including tumor heterogeneity, antigen escape, and an immunosuppressive microenvironment. Here, we found that SNU398, a hepatocellular carcinoma (HCC) cell line, exhibited high expression levels of fibroblast activation protein (FAP) and Glypican 3 (GPC3), which were negatively correlated with patient prognosis. The HepG2 HCC cell line highly expressed GPC3, while the SNU387 cell line exhibited high expression of FAP. Thus, we developed bispecific CAR-T cells to simultaneously target FAP and GPC3 to address tumor heterogeneity in HCC. The anti-FAP-GPC3 bispecific CAR-T cells could recognize and be activated by FAP or GPC3 expressed by tumor cells. Compared with anti-FAP CAR-T cells or anti-GPC3 CAR-T cells, bispecific CAR-T cells achieved more robust activity against tumor cells expressing FAP and GPC3 . The anti-FAP-GPC3 bispecific CAR-T cells also exhibited superior antitumor efficacy and significantly prolonged the survival of mice compared with single-target CAR-T cells . Overall, the use of anti-FAP-GPC3 bispecific CAR-T cells is a promising treatment approach to reduce tumor recurrence caused by tumor antigen heterogeneity.
嵌合抗原受体（CAR）T细胞疗法已在治疗血液系统恶性肿瘤方面显示出强大疗效，但在治疗实体瘤方面仍存在一些挑战，包括肿瘤异质性、抗原逃逸和免疫抑制微环境。在此，我们发现肝癌细胞系SNU398中，成纤维细胞激活蛋白（FAP）和磷脂酰肌醇蛋白聚糖3（GPC3）表达水平较高，且这二者与患者预后呈负相关。肝癌细胞系HepG2中GPC3高表达，而SNU387细胞系中FAP高表达。因此，我们开发了双特异性CAR-T细胞以同时靶向FAP和GPC3，从而应对肝癌中的肿瘤异质性问题。抗FAP-GPC3双特异性CAR-T细胞能够识别由肿瘤细胞表达的FAP或GPC3并被激活。与抗FAP CAR-T细胞或抗GPC3 CAR-T细胞相比，双特异性CAR-T细胞对表达FAP和GPC3的肿瘤细胞具有更强的活性。与单靶点CAR-T细胞相比，抗FAP-GPC3双特异性CAR-T细胞还表现出卓越的抗肿瘤疗效，并显著延长了小鼠的生存期。总体而言，使用抗FAP-GPC3双特异性CAR-T细胞是一种有前景的治疗方法，可减少由肿瘤抗原异质性导致的肿瘤复发。
