Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies

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 and Lili Yang ()
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Yan-Ruide Li: University of California
Ying Fang: University of California
Siyue Niu: University of California
Yichen Zhu: University of California
Yuning Chen: University of California
Zibai Lyu: University of California
Enbo Zhu: University of California
Yanxin Tian: University of California
Jie Huang: University of California
Valerie Rezek: University of California
Scott Kitchen: University of California
Tzung Hsiai: University of California
Jin J. Zhou: University of California
Pin Wang: University of Southern California
Wanxing Chai-Ho: University of California
Sunmin Park: University of California
Christopher S. Seet: University of California
Caspian Oliai: University of California
Lili Yang: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-28

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56270-6

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