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<p>Although chimeric antigen receptor (CAR)-T cells are promising effector cells to treat hematologic tumors, developing effective CAR-T cells for solid tumors remains challenging. Dickkopf-1 (DKK1) protein is widely expressed by human hematologic and solid tumors. Using the sequence of murine or humanized monoclonal antibody recognizing DKK1-A2 complexes (DKK1-P20 peptide in the context of HLA-A*0201) that are detected on all examined HLA-A2<sup>+</sup> tumor samples but not normal tissues except tonsils, we generate DKK1-A2 CAR-T cells that specifically and effectively lyse HLA-A2- and DKK1-expressing tumor cells but not blood or bone marrow cells from HLA-A2<sup>+</sup> healthy donors. In xenograft models of human myeloma, pancreatic, lung, and breast cancers and patient-derived xenograft of pancreatic cancer, DKK1-A2 but not CD19 CAR-T cells effectively control or eradicate established tumors without detectable toxicities in NSG or human DKK1 and HLA-A2-trangenic mice. This study indicates that DKK1-A2 CAR-T cells may be used to treat human cancers.</p>

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T cells engineered against Dickkopf-1-A2 complex can be used to treat HLA-A2+ solid and hematologic cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月16日

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  • Yufei Zhang,
  • Wei Xiong,
  • Jianfei Qian,
  • Rui Duan,
  • Qi Guo,
  • Qiang Wang,
  • Wei Wu,
  • Chuanchao Zhang,
  • Yabo Li,
  • Miao Xian,
  • Yong Lu,
  • Nestor F. Esnaola,
  • Jenny C. Chang,
  • Liuling Xiao,
  • Ling Zhong,
  • Qing Yi

摘要

Although chimeric antigen receptor (CAR)-T cells are promising effector cells to treat hematologic tumors, developing effective CAR-T cells for solid tumors remains challenging. Dickkopf-1 (DKK1) protein is widely expressed by human hematologic and solid tumors. Using the sequence of murine or humanized monoclonal antibody recognizing DKK1-A2 complexes (DKK1-P20 peptide in the context of HLA-A*0201) that are detected on all examined HLA-A2+ tumor samples but not normal tissues except tonsils, we generate DKK1-A2 CAR-T cells that specifically and effectively lyse HLA-A2- and DKK1-expressing tumor cells but not blood or bone marrow cells from HLA-A2+ healthy donors. In xenograft models of human myeloma, pancreatic, lung, and breast cancers and patient-derived xenograft of pancreatic cancer, DKK1-A2 but not CD19 CAR-T cells effectively control or eradicate established tumors without detectable toxicities in NSG or human DKK1 and HLA-A2-trangenic mice. This study indicates that DKK1-A2 CAR-T cells may be used to treat human cancers.