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Stable Transduction of the Interleukin-2 Gene Into Human Natural
Killer Cell Lines and Their Phenotypic and Functional Characterization
In Vitro and In Vivo
Shigeki Nagashima,
Robbie Mailliard,
Yoshiro Kashii,
Torsten E. Reichert,
Ronald B. Herberman,
Paul Robbins, and
Theresa L. Whiteside
From the Departments of Pathology, Otolaryngology, Medicine, and
Biochemistry/Molecular Biology, University of Pittsburgh School of
Medicine, Pittsburgh, PA; and University of Pittsburgh Cancer
Institute, Pittsburgh, PA.
A variety of strategies have been attempted in the past to stably
transduce natural killer (NK) cells with cytokine or other cellular
genes. Here, we demonstrate the successful delivery of the
interleukin-2 (IL-2) gene into two human NK cell lines, IL-2-dependent NK-92 and IL-2-independent YT, by retroviral transduction. An MuLV-based retroviral vector expressing human IL-2 and
neor markers from a polycistronic message was
constructed and transduced into a CRIP packaging cell line. By
coincubation of NK cells with monolayers of CRIP cells or by using
retrovirus-containing supernatants in a flow-through method, 10% to
20% of NK cells were stably transduced. Upon selection in the presence
of increasing G418 concentrations, transduced NK cells were able to
proliferate independently of IL-2 for more than 5 months and to secrete
up to 5.5 ng/106 cells/24 h of IL-2. IL-2 gene-transduced
NK-92 cells had an in vitro cytotoxicity against tumor targets that was
significantly higher than that of parental cells and secreted
interferon gamma (IFN ) and tumor necrosis factor alpha (TNF ) in
addition to IL-2. Moreover, the in vivo antitumor activity of IL-2
gene-transduced NK-92 cells against established 3-day liver metastases
in mice was greater than that of parental nontransduced NK cells.
Stable expression of the IL-2 transgene in NK cells improved their
therapeutic potential in tumor-bearing hosts. Thus, transduced NK cells
secreted sufficient quantities of bioactive IL-2 to proliferate in
vitro and mediated the antitumor effects both in vitro and in vivo in the absence of exogenous IL-2. These results suggest that genetic modification of NK cells ex vivo could be useful for clinical cancer
therapy in the future.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3850-3861
© 1998 by The American Society of Hematology.
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