Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies
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.
Authors
- Yichen Zhu (ORCID: https://orcid.org/0000-0002-8772-2860)
- Lili Yang (ORCID: https://orcid.org/0000-0001-6568-0404)
- Enbo Zhu (ORCID: https://orcid.org/0000-0001-8600-8553)
- Caspian Oliai (ORCID: https://orcid.org/0000-0002-6368-8557)
- Ying Fang (ORCID: https://orcid.org/0009-0006-1018-5450)
- Jie Huang (ORCID: https://orcid.org/0000-0002-0348-6590)
- Christopher S. Seet (ORCID: https://orcid.org/0000-0002-4821-1400)
- Scott G. Kitchen (ORCID: https://orcid.org/0000-0001-6182-6082)
- Wanxing Chai‐Ho (ORCID: https://orcid.org/0000-0002-0657-836X)
- Yan-Ruide Li (ORCID: https://orcid.org/0000-0002-9858-300X)
- Shaoqiang Niu
- Valerie Rezek (ORCID: https://orcid.org/0000-0002-2336-7599)
- Tzung K. Hsiai (ORCID: https://orcid.org/0000-0003-1734-0792)
- Jin Zhou (ORCID: https://orcid.org/0000-0001-7983-0274)
- Soo‐Jin Park (ORCID: https://orcid.org/0000-0002-6350-6135)
- Pin Wang (ORCID: https://orcid.org/0000-0002-4132-105X)
- Yuning Chen (ORCID: https://orcid.org/0009-0000-8010-670X)
- Yanxin Tian
- Zibai Lyu
Institutions
- University of Southern California (US)
- University of California, Los Angeles (US)
- Black AIDS Institute (US)
- Parker Institute for Cancer Immunotherapy (US)
- Broad Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1038/s41467-025-56270-6
- Citations
- 37
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 38.68
Funders
- U.S. Department of Defense
- California Institute for Regenerative Medicine
- University of California, Los Angeles