Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 61, Issue 9, Pages 1451-1461Publisher
SPRINGER
DOI: 10.1007/s00262-012-1212-x
Keywords
Interleukin-15; Natural killer cells; Lentiviral vector; scFv antibody; Chimeric antigen receptor; EpCAM
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Funding
- Bundesministerium fur Bildung und Forschung (BMBF) [FKZ 01GU0805]
- Deutsche Forschungsgemeinschaft (DFG) [GRK1172]
- LOEWE Center for Cell and Gene Therapy Frankfurt (CGT)
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Natural killer (NK) cells hold promise for adoptive cancer immunotherapy but are dependent on cytokines such as interleukin (IL)-2 for growth and cytotoxicity. Here, we investigated the consequences of ectopic expression of IL-15 in human NK cells. IL-2 and IL-15 belong to the common gamma chain family of cytokines and have overlapping activities. Transduction of clinically applicable NK-92 cells with lentiviral vectors encoding human IL-15 resulted in predominantly intracellular expression of the cytokine, and STAT5 activation, proliferation and cytotoxicity of the producer cells in the absence of IL-2. Growth of non-transduced bystander cells was not supported, allowing rapid enrichment of gene-modified cells solely by IL-2 withdrawal. This was also the case upon transduction of NK-92 and NKL cells with a bicistronic lentiviral vector encoding IL-15 and a chimeric antigen receptor (CAR) targeting the pancarcinoma antigen EpCAM. Effector cells co-expressing CAR and IL-15 continued to proliferate in the absence of exogenous cytokines and displayed high and selective cell-killing activity against EpCAM-expressing breast carcinoma cells that were resistant to the natural cytotoxicity of unmodified NK cells. This strategy facilitates rapid isolation and continuous expansion of retargeted NK cells and may extend their potential clinical utility.
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