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ORIGINAL RESEARCH article

Front. Immunol.
Sec. T Cell Biology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1541653
This article is part of the Research Topic Expanding CAR-T Cell Therapy: Breakthroughs from Cancer to Autoimmune Diseases View all 6 articles

Unleashing the Potential of a Low CpG Passer Transposon for Superior CAR-T Cell Therapy

Provisionally accepted
Jianyao Zeng Jianyao Zeng 1Yan Sun Yan Sun 1,2Yuan Fang Yuan Fang 2Xiaodie Wang Xiaodie Wang 1*Qian Huang Qian Huang 2*Pingjing Zhang Pingjing Zhang 2*Meiqi Shao Meiqi Shao 2*Pei Wang Pei Wang 2*Jingbo Cheng Jingbo Cheng 2*Meng Di Meng Di 1*Tao Liu Tao Liu 2*Qijun Qian Qijun Qian 1,2,3*
  • 1 Shanghai University, Shanghai, China
  • 2 Shanghai Cell Therapy Group Co Ltd, Shanghai, China
  • 3 Shanghai Mengchao Cancer Hospital, Shanghai, China

The final, formatted version of the article will be published soon.

    To date, the non-viral vector Chimeric Antigen Receptor (CAR) T cell preparation platform, exemplified by transposons, has demonstrated significant potential in tumor immunotherapy and yielded positive results in multiple clinical trials. Nonetheless, 2 non-methylated CpG sequences within plasmid DNA can elicit an inflammatory response via Toll-like receptor 9 (TLR9) during CAR-T cell preparation, adversely affecting transgene expression. Additionally, de novo DNA methylation programs promote T cell exhaustion, which poses a significant limitation for CAR-T cell therapy applications. In this study, we modified the newly discovered Passer (JL) transposon to construct a low-CpG content transposon for CAR-T cell (LCG CAR-T cell) preparation. In vitro experiments demonstrated that LCG CAR-T cells prepared using this new transposon exhibited stronger cytotoxicity. In animal models, LCG CAR-T cells significantly inhibited tumor growth and increased the populations of CD4+CAR-T cells and tumor-infiltrating lymphocytes. Furthermore, LCG CAR-T cells modulated pro-inflammatory cytokine release, thereby reducing in vivo inflammatory responses and surpassing the effects observed with unmodified CAR-T cells. Collectively, our results demonstrate the high safety and efficacy of non-viral, low CpG Passer transposon CAR-T cells, offering new avenues for improving CAR-T cell efficacy while minimizing in vivo inflammation.

    Keywords: Methylation, CpG motif, Chimeric antigen receptor T cell, Transposon, Inflammation

    Received: 08 Dec 2024; Accepted: 15 Jan 2025.

    Copyright: © 2025 Zeng, Sun, Fang, Wang, Huang, Zhang, Shao, Wang, Cheng, Di, Liu and Qian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Xiaodie Wang, Shanghai University, Shanghai, China
    Qian Huang, Shanghai Cell Therapy Group Co Ltd, Shanghai, China
    Pingjing Zhang, Shanghai Cell Therapy Group Co Ltd, Shanghai, China
    Meiqi Shao, Shanghai Cell Therapy Group Co Ltd, Shanghai, China
    Pei Wang, Shanghai Cell Therapy Group Co Ltd, Shanghai, China
    Jingbo Cheng, Shanghai Cell Therapy Group Co Ltd, Shanghai, China
    Meng Di, Shanghai University, Shanghai, China
    Tao Liu, Shanghai Cell Therapy Group Co Ltd, Shanghai, China
    Qijun Qian, Shanghai University, Shanghai, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.