Targeted delivery of a PD-1-blocking scFv by CD133-specific CAR-T cells using nonviral Sleeping Beauty transposition shows enhanced antitumour efficacy for advanced hepatocellular carcinoma

BMC Medicine

Research Article

Haoran Zhong¹  Xinyi Yang²  Tong Xiang²  Yongqiang Li²  Fengze Sun²  Yuanyuan Chen²  Jinqi You²  Hao Chen²  Jieying Yang²  Yufei Du²  Desheng Weng²  Jianchuan Xia²  Dijun Ouyang²  Qiuzhong Pan²  Chaopin Yang²  Yan Tang²  Qijing Wang²  Yue Huang²  Yulong Han²  Jiamei Gu³  Yizhi Wang⁴  Liming Cai⁵  Zhongqiu Liu⁵ 

[1] Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, Guangdong, People’s Republic of China;Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, Guangdong, People’s Republic of China;Department of Biotherapy, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, Guangdong, People’s Republic of China;Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, Guangdong, People’s Republic of China;Department of Molecular Diagnostics, Sun Yat-Sen University, Cancer Center, 510060, Guangzhou, Guangdong, People’s Republic of China;Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, Guangdong, People’s Republic of China;Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, Guangdong, People’s Republic of China;International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, 510060, Guangzhou, Guangdong, People’s Republic of China;

关键词: Sleeping Beauty system;    Minicircle;    CAR-T;    CD133;    PD-1;    Hepatocellular carcinoma;   

DOI  :  10.1186/s12916-023-03016-0

 received in 2022-06-12, accepted in 2023-07-31,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCD133 is considered a marker for cancer stem cells (CSCs) in several types of tumours, including hepatocellular carcinoma (HCC). Chimeric antigen receptor-specific T (CAR-T) cells targeting CD133-positive CSCs have emerged as a tool for the clinical treatment of HCC, but immunogenicity, the high cost of clinical-grade recombinant viral vectors and potential insertional mutagenesis limit their clinical application.MethodsCD133-specific CAR-T cells secreting PD-1 blocking scFv (CD133 CAR-T and PD-1 s cells) were constructed using a sleeping beauty transposon system from minicircle technology, and the antitumour efficacy of CD133 CAR-T and PD-1 s cells was analysed in vitro and in vivo.ResultsA univariate analysis showed that CD133 expression in male patients at the late stage (II and III) was significantly associated with worse progression-free survival (PFS) (P = 0.0057) and overall survival (OS) (P = 0.015), and a multivariate analysis showed a trend toward worse OS (P = 0.041). Male patients with advanced HCC exhibited an approximately 20-fold higher PD-L1 combined positive score (CPS) compared with those with HCC at an early stage. We successfully generated CD133 CAR-T and PD-1 s cells that could secrete PD-1 blocking scFv based on a sleeping beauty system involving minicircle vectors. CD133 CAR-T and PD-1 s cells exhibited significant antitumour activity against HCC in vitro and in xenograft mouse models. Thus, CD133 CAR-T and PD-1 s cells may be a therapeutically tractable strategy for targeting CD133-positive CSCs in male patients with advanced HCC.ConclusionsOur study provides a nonviral strategy for constructing CAR-T cells that could also secrete checkpoint blockade inhibitors based on a Sleeping Beauty system from minicircle vectors and revealed a potential benefit of this strategy for male patients with advanced HCC and high CD133 expression (median immunohistochemistry score > 2.284).

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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