期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 94, 期 1, 页码 83-93出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00109-015-1327-6
关键词
Gene therapy; Alpharetrovirus; Natural killer cells; Immunotherapy; Chimeric antigen receptor; Leukemia
资金
- Deutsche Forschungsgemeinschaft [SFB738, SPP1230]
- Deutsche Forschungsgemeinschaft (Cluster of Excellence RE-BIRTH) [EXC 62/1]
- Bundesministerium fur Bildung und Forschung (BMBF, Joint Research Project IFB-Tx, PidNet) [01E00802]
- DAAD (Modern Applications in Biotechnology)
- European Union (FP7 project PERSIST)
Natural killer (NK) cells play an important role in tumor immunotherapy with their unique capability of killing transformed cells without the need for prior sensitization and without major histocompatibility complex (MHC)/peptide restriction. However, tumor cells can escape NK cell cytotoxicity by various tumor immune escape mechanisms. To overcome these escape mechanisms, NK cells can be modified to express chimeric antigen receptors (CARs), enhancing their tumor-specific cytotoxicity. To determine the most efficacious method to modify human NK cells, we compared different retroviral vector systems, retroviral pseudotypes, and transduction protocols. Using optimized transduction conditions, the highest transduction levels (up to 60 %) were achieved with alpharetroviral vectors. Alpharetroviral-modified primary human NK cells exhibited no alteration in receptor expression and had similar degranulation activity as untransduced NK cells, thus demonstrating that alpharetroviral modification did not negatively affect NK cell cytotoxicity. Transduction of NK cells with an alpharetroviral vector containing a CD19 CAR expression cassette selectively enhanced NK cell cytotoxicity towards CD19-expressing leukemia cells, achieving nearly complete elimination of leukemia cells after 48 h. Taken together, alpharetroviral vectors are promising tools for NK cell-mediated cancer immunotherapy applications.
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