Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies
Abstract Chimeric antigen receptor (CAR)-engineered T cell therapy holds promise for treating myeloid malignancies, but challenges remain in bone marrow (BM) infiltration and targeting BM-resident malignant cells. Current autologous CAR-T therapies also face manufacturing and patient selection issue...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56270-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571498831806464 |
|---|---|
| author | Yan-Ruide Li Ying Fang Siyue Niu Yichen Zhu Yuning Chen Zibai Lyu Enbo Zhu Yanxin Tian Jie Huang Valerie Rezek Scott Kitchen Tzung Hsiai Jin J. Zhou Pin Wang Wanxing Chai-Ho Sunmin Park Christopher S. Seet Caspian Oliai Lili Yang |
| author_facet | Yan-Ruide Li Ying Fang Siyue Niu Yichen Zhu Yuning Chen Zibai Lyu Enbo Zhu Yanxin Tian Jie Huang Valerie Rezek Scott Kitchen Tzung Hsiai Jin J. Zhou Pin Wang Wanxing Chai-Ho Sunmin Park Christopher S. Seet Caspian Oliai Lili Yang |
| author_sort | Yan-Ruide Li |
| collection | DOAJ |
| description | Abstract Chimeric antigen receptor (CAR)-engineered T cell therapy holds promise for treating myeloid malignancies, but challenges remain in bone marrow (BM) infiltration and targeting BM-resident malignant cells. Current autologous CAR-T therapies also face manufacturing and patient selection issues, underscoring the need for off-the-shelf products. In this study, we characterize primary patient samples and identify a unique therapeutic opportunity for CAR-engineered invariant natural killer T (CAR-NKT) cells. Using stem cell gene engineering and a clinically guided culture method, we generate allogeneic CD33-directed CAR-NKT cells with high yield, purity, and robustness. In preclinical mouse models, CAR-NKT cells exhibit strong BM homing and effectively target BM-resident malignant blast cells, including CD33-low/negative leukemia stem and progenitor cells. Furthermore, CAR-NKT cells synergize with hypomethylating agents, enhancing tumor-killing efficacy. These cells also show minimal off-tumor toxicity, reduced graft-versus-host disease and cytokine release syndrome risks, and resistance to allorejection, highlighting their substantial therapeutic potential for treating myeloid malignancies. |
| format | Article |
| id | doaj-art-20e57e83f91a49ceb053602812fe87bc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-20e57e83f91a49ceb053602812fe87bc2025-02-02T12:31:57ZengNature PortfolioNature Communications2041-17232025-02-0116112810.1038/s41467-025-56270-6Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignanciesYan-Ruide Li0Ying Fang1Siyue Niu2Yichen Zhu3Yuning Chen4Zibai Lyu5Enbo Zhu6Yanxin Tian7Jie Huang8Valerie Rezek9Scott Kitchen10Tzung Hsiai11Jin J. Zhou12Pin Wang13Wanxing Chai-Ho14Sunmin Park15Christopher S. Seet16Caspian Oliai17Lili Yang18Department of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDivision of Cardiology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDepartment of Biostatistics, Fielding School of Public Health, University of CaliforniaDepartment of Chemical Engineering and Materials Science, University of Southern CaliforniaDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaDepartment of Microbiology, Immunology & Molecular Genetics, University of CaliforniaAbstract Chimeric antigen receptor (CAR)-engineered T cell therapy holds promise for treating myeloid malignancies, but challenges remain in bone marrow (BM) infiltration and targeting BM-resident malignant cells. Current autologous CAR-T therapies also face manufacturing and patient selection issues, underscoring the need for off-the-shelf products. In this study, we characterize primary patient samples and identify a unique therapeutic opportunity for CAR-engineered invariant natural killer T (CAR-NKT) cells. Using stem cell gene engineering and a clinically guided culture method, we generate allogeneic CD33-directed CAR-NKT cells with high yield, purity, and robustness. In preclinical mouse models, CAR-NKT cells exhibit strong BM homing and effectively target BM-resident malignant blast cells, including CD33-low/negative leukemia stem and progenitor cells. Furthermore, CAR-NKT cells synergize with hypomethylating agents, enhancing tumor-killing efficacy. These cells also show minimal off-tumor toxicity, reduced graft-versus-host disease and cytokine release syndrome risks, and resistance to allorejection, highlighting their substantial therapeutic potential for treating myeloid malignancies.https://doi.org/10.1038/s41467-025-56270-6 |
| spellingShingle | Yan-Ruide Li Ying Fang Siyue Niu Yichen Zhu Yuning Chen Zibai Lyu Enbo Zhu Yanxin Tian Jie Huang Valerie Rezek Scott Kitchen Tzung Hsiai Jin J. Zhou Pin Wang Wanxing Chai-Ho Sunmin Park Christopher S. Seet Caspian Oliai Lili Yang Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies Nature Communications |
| title | Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies |
| title_full | Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies |
| title_fullStr | Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies |
| title_full_unstemmed | Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies |
| title_short | Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies |
| title_sort | allogeneic cd33 directed car nkt cells for the treatment of bone marrow resident myeloid malignancies |
| url | https://doi.org/10.1038/s41467-025-56270-6 |
| work_keys_str_mv | AT yanruideli allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT yingfang allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT siyueniu allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT yichenzhu allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT yuningchen allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT zibailyu allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT enbozhu allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT yanxintian allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT jiehuang allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT valerierezek allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT scottkitchen allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT tzunghsiai allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT jinjzhou allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT pinwang allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT wanxingchaiho allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT sunminpark allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT christophersseet allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT caspianoliai allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies AT liliyang allogeneiccd33directedcarnktcellsforthetreatmentofbonemarrowresidentmyeloidmalignancies |