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!
|
| Summary: | 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. |
|---|---|
| ISSN: | 2041-1723 |