To treat bone marrow (BM) myeloid malignancies, such as AML and MDS, Li, Fang, Niu, and Zhu et al. generated allogeneic, CD33-targeted, IL-15-expressing CAR-NKT (engineered from cord blood stem cells) using a scalable, clinically relevant (yield and purity) culture method. Compared to CD33-CAR-T cells, CD33-CAR-NKT cells efficiently homed to the BM and killed BM-resident malignant blast cells, including CD33-low/negative leukemic progenitors. CAR-NKT cells synergized with hypomethylating agents to enhance efficacy, and exhibited a favorable safety profile, with decreased GvHD and CRS, and resistance to allograft rejection.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles
Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (2) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (3) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (4) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (5) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (6) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (7) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (8) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (9) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. Department of Bioengineering, University of California, Los Angeles, CA, USA. (10) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (11) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (12) Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (13) Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA. (14) Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA. (15) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (16) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (17) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA. Molecular Biology Institute, University of California, Los Angeles, CA, USA. (18) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (19) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. Department of Bioengineering, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. Molecular Biology Institute, University of California, Los Angeles, CA, USA. liliyang@ucla.edu. Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, CA, USA. liliyang@ucla.edu.
