Related Experiment Video
Updated: Feb 18, 2026
Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
T cells engineered against Dickkopf-1-A2 complex can be used to treat HLA-A2+ solid and hematologic cancers
Yufei Zhang1, Wei Xiong1, Jianfei Qian1
1Center for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
Abstract:
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.
Insights
New chimeric antigen receptor (CAR)-T cells targeting Dickkopf-1 (DKK1) protein show promise for solid tumors. DKK1-A2 CAR-T cells effectively eliminated various cancers in models without significant toxicity.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy is effective for hematologic tumors but faces challenges in solid tumors.
- Dickkopf-1 (DKK1) protein is a promising target as it is expressed on many hematologic and solid tumors.
- HLA-A2 is a common human leukocyte antigen found on tumor cells.
Purpose of the Study:
- To develop and evaluate DKK1-A2 CAR-T cells for targeting solid tumors expressing DKK1 and HLA-A2.
- To assess the efficacy and safety of DKK1-A2 CAR-T cells in preclinical cancer models.
Main Methods:
- Generated DKK1-A2 CAR-T cells using antibodies targeting DKK1-A2 complexes.
- Tested CAR-T cell specificity against HLA-A2+ tumor cells and healthy donor cells.
- Evaluated DKK1-A2 CAR-T cell efficacy in xenograft models of human myeloma, pancreatic, lung, and breast cancers.
Main Results:
- DKK1-A2 CAR-T cells specifically lysed HLA-A2- and DKK1-expressing tumor cells.
- No lysis of blood or bone marrow cells from healthy HLA-A2+ donors was observed.
- DKK1-A2 CAR-T cells controlled or eradicated established tumors in various xenograft models.
- No detectable toxicities were observed in NSG or transgenic mice models.
Conclusions:
- DKK1-A2 CAR-T cells demonstrate specific and effective anti-tumor activity against solid tumors.
- These CAR-T cells represent a potential new therapeutic strategy for treating DKK1- and HLA-A2-expressing human cancers.
- Further clinical investigation of DKK1-A2 CAR-T cells is warranted.
