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Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy.
Li, Yan-Ruide; Zhou, Yang; Yu, Jiaji; Zhu, Yichen; Lee, Derek; Zhu, Enbo; Li, Zhe; Kim, Yu Jeong; Zhou, Kuangyi; Fang, Ying; Lyu, Zibai; Chen, Yuning; Tian, Yanxin; Huang, Jie; Cen, Xinjian; Husman, Tiffany; Cho, Jae Min; Hsiai, Tzung; Zhou, Jin J; Wang, Pin; Puliafito, Benjamin R; Larson, Sarah M; Yang, Lili.
Afiliación
  • Li YR; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Zhou Y; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Yu J; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Zhu Y; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Lee D; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Zhu E; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Li Z; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Kim YJ; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Zhou K; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Fang Y; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Lyu Z; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Chen Y; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Tian Y; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Huang J; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Cen X; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Husman T; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Cho JM; Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Hsiai T; Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Zhou JJ; Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Wang P; Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
  • Puliafito BR; Department of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Larson SM; Department of Internal Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Yang L; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Centre of Regenerative Medicine and Stem Ce
Mol Ther ; 32(6): 1849-1874, 2024 Jun 05.
Article en En | MEDLINE | ID: mdl-38584391
ABSTRACT
The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Inmunoterapia Adoptiva / Células T Asesinas Naturales / Receptores Quiméricos de Antígenos Límite: Animals / Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Inmunoterapia Adoptiva / Células T Asesinas Naturales / Receptores Quiméricos de Antígenos Límite: Animals / Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos