PDF(Pubmed)
Abstract：
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 in vitro. 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 in vivo. 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.
摘要：
嵌合抗原受体（CAR）T细胞疗法已证明对血液恶性肿瘤的强大功效，但是在治疗实体肿瘤方面仍然存在一些挑战，包括肿瘤异质性，抗原逃逸,和免疫抑制微环境。这里,我们发现SNU398，一种肝细胞癌（HCC）细胞系，高表达成纤维细胞活化蛋白（FAP）和磷脂酰肌醇蛋白聚糖3（GPC3），与患者预后呈负相关。HepG2HCC细胞系高表达GPC3，而SNU387细胞系高表达FAP。因此，我们开发了双特异性CAR-T细胞以同时靶向FAP和GPC3来解决HCC中的肿瘤异质性。抗FAP-GPC3双特异性CAR-T细胞可以识别并被肿瘤细胞表达的FAP或GPC3激活。与抗FAPCAR-T细胞或抗GPC3CAR-T细胞相比，双特异性CAR-T细胞在体外对表达FAP和GPC3的肿瘤细胞实现了更强的活性。抗FAP-GPC3双特异性CAR-T细胞还表现出优异的抗肿瘤功效,并且在体内与单靶标CAR-T细胞相比显著延长小鼠的存活。总的来说,使用抗FAP-GPC3双特异性CAR-T细胞是减少由肿瘤抗原异质性引起的肿瘤复发的有前景的治疗方法.
