| Autor: |
Chaopin Yang, Jinqi You, Qiuzhong Pan, Yan Tang, Liming Cai, Yue Huang, Jiamei Gu, Yizhi Wang, Xinyi Yang, Yufei Du, Dijun Ouyang, Hao Chen, Haoran Zhong, Yongqiang Li, Jieying Yang, Yulong Han, Fengze Sun, Yuanyuan Chen, Qijing Wang, Desheng Weng, Zhongqiu Liu, Tong Xiang, Jianchuan Xia |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
BMC Medicine, Vol 21, Iss 1, Pp 1-19 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1741-7015 |
| DOI: |
10.1186/s12916-023-03016-0 |
| Popis: |
Abstract Background CD133 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. Methods CD133-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. Results A 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. Conclusions Our 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). |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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