CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma.
Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells. In vitro, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-γ (IFN-γ) production, and showed a specific CS1-dependent recognition of MM cells. Ex vivo, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM.
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Chu
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing, PR China.
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Deng
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Benson
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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He
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Hughes
Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
J
J
Zhang
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Peng
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Mao
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Yi
1] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [2] Department of Pathology, The Ohio State University, Columbus, OH, USA.
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Ghoshal
1] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [2] Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.
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He
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [3] Blood and Marrow Transplantation Program, The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.
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Devine
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, 3005 Science and Engineering Research Center, University of Houston, Houston, TX, USA.
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Zhang
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Caligiuri
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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Hofmeister
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [3] Blood and Marrow Transplantation Program, The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.
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Yu
D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005818:Genetic Engineering; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D009101:Multiple Myeloma / Q000401:mortality / Q000628:therapy*; D010641:Phenotype; D011946:Receptors, Antigen / Q000235:genetics*; D011971:Receptors, Immunologic / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family; D023041:Xenograft Model Antitumor Assays
D011946:Receptors, Antigen; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D007371:Interferon-gamma