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Allogeneic HSPC-engineered CD33-targeting CAR-NKT cells synergize with hypomethylating agents for effective and safe treatment of myeloid malignancies

ABSTRACT: Chimeric antigen receptor (CAR)-engineered T cell therapy holds promise for targeting myeloid malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, autologous approaches pose significant challenges in manufacturing and patient selection, emphasizing the need for off-the-shelf cell products. In this study, we systematically characterized primary AML and MDS patient samples, identifying a unique therapeutic opportunity for CAR-engineered invariant natural killer T (CAR-NKT) cell therapy. Utilizing a clinically guided culture method, we generated allogeneic IL-15-enhanced CD33-targeting CAR-NKT (Allo15CAR33-NKT) cells through HSPC engineering and an ex vivo, feeder-free HSPC differentiation culture. These cells demonstrated potent antitumor efficacy against blast cells via multiple tumor-targeting mechanisms. In vivo, Allo15CAR33-NKT cells exhibited effective tumor homing, expansion, and persistence, characterized by high effector function and low exhaustion propensity. Furthermore, these cells synergized with hypomethylating agent (HMA) treatment, which upregulated CD1d and NK ligand expression on tumor cells, enhancing susceptibility to Allo15CAR33-NKT cell-mediated killing. Notably, Allo15CAR33-NKT cells displayed minimal off-tumor effects against hematopoietic precursors, and low risks of graft-versus-host disease and cytokine release syndrome, highlighting their substantial therapeutic potential for myeloid malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270430 | GEO | 2025/01/01

REPOSITORIES: GEO

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Allogeneic HSPC-engineered CD33-targeting CAR-NKT cells synergize with hypomethylating agents for effective and safe treatment of myeloid malignancies

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