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- Title
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.
- Authors
Yang, Chaopin; You, Jinqi; Pan, Qiuzhong; Tang, Yan; Cai, Liming; Huang, Yue; Gu, Jiamei; Wang, Yizhi; Yang, Xinyi; Du, Yufei; Ouyang, Dijun; Chen, Hao; Zhong, Haoran; Li, Yongqiang; Yang, Jieying; Han, Yulong; Sun, Fengze; Chen, Yuanyuan; Wang, Qijing; Weng, Desheng
- 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).
- Subjects
TRANSPOSONS; HEPATOCELLULAR carcinoma; CANCER stem cells; GENETIC vectors; PROGRAMMED cell death 1 receptors
- Publication
BMC Medicine, 2023, Vol 21, Issue 1, p1
- ISSN
1741-7015
- Publication type
Article
- DOI
10.1186/s12916-023-03016-0