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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1504459

Hypoimmunogenic CD19 CAR-NK cells derived from embryonic stem cells suppress the progression of human B-cell malignancies in xenograft animals

Provisionally accepted
Tongjie Wang Tongjie Wang 1*Qi Zhang Qi Zhang 1Chengxiang Xia Chengxiang Xia 2Qitong Weng Qitong Weng 1Leqiang Zhang Leqiang Zhang 1Yao Wang Yao Wang 1Yanhong Liu Yanhong Liu 1Xiujuan Zheng Xiujuan Zheng 1Yunqing Lin Yunqing Lin 1Yi Chen Yi Chen 2Yiyuan Shen Yiyuan Shen 2Hanmeng Qi Hanmeng Qi 2Lijuan Liu Lijuan Liu 1Yanping Zhu Yanping Zhu 1Min Zhang Min Zhang 1Dehao Huang Dehao Huang 1Fangxiao Hu Fangxiao Hu 2Mengyun Zhang Mengyun Zhang 1Hui Zeng Hui Zeng 3Jinyong Wang Jinyong Wang 1
  • 1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
  • 2 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
  • 3 Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, China

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

    Background: Chimeric antigen receptor (CAR) engineered natural killer (NK) cells exhibit advantages such as MHC-independent recognition and strong anti-tumor functions. However, allogeneic CAR-NK cells derived from human tissues are heterogeneous and susceptible to clearance by hosts. Methods: We generated a B2M knockout, HLA-E and CD19 CAR ectopic expressing embryonic stem cell (ESC) line, which differentiated normally and gave rise to homogeneous CD19 CAR-NK (CD19 CAR-UiNK) cells using an organoid aggregate induction method. The CD19 CAR-UiNK were co-cultured with T cells or NK cells derived from peripheral blood mononuclear cells (PBMC) with the mismatched HLA to evaluate the immunogenicity of CD19 CAR-UiNK cells. We further assessed the therapeutic effects of CD19 CAR-UiNK cells on CD19 + tumor cells through in vitro cytotoxicity assays and in vivo animal models. Results: The CD19 CAR-UiNK cells exhibited typical expression patterns of activating and inhibitory receptors, and crucial effector molecules of NK cells, similar to those of unmodified NK cells. In co-culture assays, the CD19 CAR-UiNK cells evaded allogeneic T cell response and suppressed allogeneic NK cell response. Functionally, the CD19 CAR-UiNK cells robustly secreted IFN-γ and TNF-α, and upregulated CD107a upon stimulation with Nalm-6 tumor cells. The CD19 CAR-UiNK cells effectively eliminated CD19 + tumor cells in vitro, including B-cell cancer cell lines and primary tumor cells from human B-cell leukemia and lymphoma. Further, the CD19 CAR-UiNK cells exhibited strong anti-tumor activity in xenograft animals.We offer a strategy for deriving homogeneous and hypoimmunogenic CD19 CAR-iNK cells with robust anti-tumor effects from ESCs. Our study has

    Keywords: Embryonic Stem Cells, CD19 CAR-NK cells, Hypoimmunogenicity, Cytotoxicity, B-cell malignancy

    Received: 30 Sep 2024; Accepted: 11 Nov 2024.

    Copyright: © 2024 Wang, Zhang, Xia, Weng, Zhang, Wang, Liu, Zheng, Lin, Chen, Shen, Qi, Liu, Zhu, Zhang, Huang, Hu, Zhang, Zeng and Wang. 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: Tongjie Wang, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 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.