Liu Xuan, Wen Jianyun, Yi Honglei, Hou Xiaorui, Yin Yue, Ye Guofu, Wu Xuedong, Jiang Xiaotao
Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Orthopedics, General Hospital of Southern Theater Command, Guangzhou, China.
Ther Adv Med Oncol. 2020 Mar 9;12:1758835920910347. doi: 10.1177/1758835920910347. eCollection 2020.
Human glypican-3 (hGPC3) is a protein highly expressed in hepatocellular carcinoma (HCC) but limited in normal tissues, making it an ideal target for immunotherapy. The adoptive transfer of hGPC3-specific chimeric antigen receptor T (CAR-T) cells for HCC treatment has been conducted in clinical trials. Due to the rigid construction, conventional CAR-T cells have some intrinsic limitations, like uncontrollable overactivation and inducing severe cytokine release syndrome.
We redesigned the hGPC3-specific CAR by splitting the traditional CAR into two parts. By using coculturing assays and a xenograft mouse model, the and cytotoxicity and cytokine release of the split anti-hGPC3 CAR-T cells were evaluated against various HCC cell lines and compared with conventional CAR-T cells.
data demonstrated that split anti-hGPC3 CAR-T cells could recognize and lyse hGPC3 HepG2 and Huh7 cells in a dose-dependent manner. Impressively, split anti-hGPC3 CAR-T cells produced and released a significantly lower amount of proinflammatory cytokines, including IFN-γ, TNF-α, IL-6, and GM-CSF, than conventional CAR-T cells. When injected into immunodeficient mice inoculated subcutaneously with HepG2 cells, our split anti-hGPC3 CAR-T cells could suppress HCC tumor growth, but released significantly lower levels of cytokines than conventional CAR-T cells.
We describe here for the first time the use of split anti-hGPC3 CAR-T cells to treat HCC; split anti-hGPC3 CAR-T cells could suppress tumor growth and reduce cytokine release, and represent a more versatile and safer alternative to conventional CAR-T cells treatment.
人磷脂酰肌醇蛋白聚糖-3（hGPC3）是一种在肝细胞癌（HCC）中高表达但在正常组织中表达受限的蛋白质，使其成为免疫治疗的理想靶点。针对HCC治疗的hGPC3特异性嵌合抗原受体T（CAR-T）细胞的过继性转移已在临床试验中进行。由于结构刚性，传统的CAR-T细胞存在一些内在局限性，如不可控的过度激活和诱导严重的细胞因子释放综合征。
我们通过将传统的CAR拆分为两部分，重新设计了hGPC3特异性CAR。通过共培养试验和异种移植小鼠模型，评估了分裂型抗hGPC3 CAR-T细胞对各种HCC细胞系的杀伤活性和细胞因子释放情况，并与传统CAR-T细胞进行比较。
数据表明，分裂型抗hGPC3 CAR-T细胞能够以剂量依赖的方式识别并裂解hGPC3阳性的HepG2和Huh7细胞。令人印象深刻的是，分裂型抗hGPC3 CAR-T细胞产生和释放的促炎细胞因子（包括IFN-γ、TNF-α、IL-6和GM-CSF）的量明显低于传统CAR-T细胞。当注射到皮下接种HepG2细胞的免疫缺陷小鼠体内时，我们的分裂型抗hGPC3 CAR-T细胞能够抑制HCC肿瘤生长，但释放的细胞因子水平明显低于传统CAR-T细胞。
我们首次描述了使用分裂型抗hGPC3 CAR-T细胞治疗HCC；分裂型抗hGPC3 CAR-T细胞能够抑制肿瘤生长并减少细胞因子释放，是传统CAR-T细胞治疗更通用、更安全的替代方案。
