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Background <p>Chimeric antigen receptor (CAR) engineered natural killer (NK) cells have shown their efficacy and superiority against cancer and possess the potential to become off-the-shelf immunotherapy products. Nonetheless, some challenges associated with CAR-NK cells still exist including inhibitory receptor engagement, antigen escape, and inadequate activation.</p> Methods <p>Given this, based on the concept of synthetic biology, we rationally designed a novel dual-targeted CAR (dtCAR), primarily comprising PD-L1 nanoantibody (PD-L1<sup>Nb</sup>) and NKG2D as the ectodomain, transmembrane and cytoplasmic domains (CP) of CD28, and the CP of 4-1BB and CD3ζ. NK92 cells were engineered to express this third-generation of dtCAR. We then elucidated the role of dtCAR-modified NK92 cells against cancer cells in vitro and in vivo.</p> Results <p>In vitro, the dtCAR-NK92 cells could still retain the characteristics of parental NK cells and exhibit improved NK cell cytotoxicity and produce more cytokines than NK92 cells when they were co-cultured with human lung cancer H1299 cells. Notably, the dtCAR-NK92 cell therapy might elicit clearance of H1299 cells by pyroptosis. Additionally, dtCAR-NK92 cells could considerably inhibit tumor growth in the human lung cancer H1299 cell tumor model.</p> Conclusions <p>We confirmed that expression of dtCAR enhanced NK92-cell activation and killing in vitro and in vivo, which provides a novel immunotherapeutic strategy for using NK-tailored CAR-engineered NK92 cells to treat human lung cancer.</p>

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CAR-NK cells with dual targeting of PD-L1 and MICA/B in lung cancer tumor models

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月25日

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  • Lingtong Zhi,
  • Zikang Zhang,
  • Qing Gao,
  • Chongye Shang,
  • Wenhui He,
  • Yuqing Wang,
  • Changjiang Guo,
  • Zhiyuan Niu,
  • Wuling Zhu

摘要

Background

Chimeric antigen receptor (CAR) engineered natural killer (NK) cells have shown their efficacy and superiority against cancer and possess the potential to become off-the-shelf immunotherapy products. Nonetheless, some challenges associated with CAR-NK cells still exist including inhibitory receptor engagement, antigen escape, and inadequate activation.

Methods

Given this, based on the concept of synthetic biology, we rationally designed a novel dual-targeted CAR (dtCAR), primarily comprising PD-L1 nanoantibody (PD-L1Nb) and NKG2D as the ectodomain, transmembrane and cytoplasmic domains (CP) of CD28, and the CP of 4-1BB and CD3ζ. NK92 cells were engineered to express this third-generation of dtCAR. We then elucidated the role of dtCAR-modified NK92 cells against cancer cells in vitro and in vivo.

Results

In vitro, the dtCAR-NK92 cells could still retain the characteristics of parental NK cells and exhibit improved NK cell cytotoxicity and produce more cytokines than NK92 cells when they were co-cultured with human lung cancer H1299 cells. Notably, the dtCAR-NK92 cell therapy might elicit clearance of H1299 cells by pyroptosis. Additionally, dtCAR-NK92 cells could considerably inhibit tumor growth in the human lung cancer H1299 cell tumor model.

Conclusions

We confirmed that expression of dtCAR enhanced NK92-cell activation and killing in vitro and in vivo, which provides a novel immunotherapeutic strategy for using NK-tailored CAR-engineered NK92 cells to treat human lung cancer.