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Leukemia. 2014 Apr;28(4):917-27. doi: 10.1038/leu.2013.279. Epub 2013 Sep 26.

CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma.

Author information

1
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.
2
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.
3
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
4
Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
5
1] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [2] Department of Pathology, The Ohio State University, Columbus, OH, USA.
6
1] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [2] Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.
7
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.
8
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, 3005 Science and Engineering Research Center, University of Houston, Houston, TX, USA.

Abstract

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.

PMID:
24067492
PMCID:
PMC3967004
DOI:
10.1038/leu.2013.279
[Indexed for MEDLINE]
Free PMC Article

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