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

Author

Listed:
  • Yan-Ruide Li

    (University of California
    University of California)

  • Ying Fang

    (University of California
    University of California)

  • Siyue Niu

    (University of California
    University of California)

  • Yichen Zhu

    (University of California
    University of California)

  • Yuning Chen

    (University of California
    University of California)

  • Zibai Lyu

    (University of California
    University of California)

  • Enbo Zhu

    (University of California
    University of California)

  • Yanxin Tian

    (University of California
    University of California)

  • Jie Huang

    (University of California
    University of California)

  • Valerie Rezek

    (University of California
    University of California
    University of California)

  • Scott Kitchen

    (University of California
    University of California
    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
    University of California
    University of California
    University of California)

  • Caspian Oliai

    (University of California)

  • Lili Yang

    (University of California
    University of California
    University of California
    University of California)

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.

Suggested Citation

  • 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-H, 2025. "Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies," Nature Communications, Nature, vol. 16(1), pages 1-28, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56270-6
    DOI: 10.1038/s41467-025-56270-6
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    References listed on IDEAS

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