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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月1日

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  • 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

摘要

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.