Journal
GENE THERAPY
Volume 9, Issue 12, Pages 786-792Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3301687
Keywords
liver metastases; gene therapy; interleukin-12; 4-1BB; co-stimulatory molecule
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Funding
- NCI NIH HHS [CA-75175, CA 70337, CA-84404] Funding Source: Medline
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We have shown that interleukin-12 (IL-12) generated a strong, albeit transient, anti-tumor response, mostly mediated by natural killer (NK) call. T cell participation, in addition to NK cells, was essential for persistence of the antitumor response. Ligation of 4-1BB, a co-stimulatory receptor expressed on activated T cells, is, known to amplify T cell-mediated immunity. In this study, we compared the effect of a systemically delivered agonistic anti-4-1BB monoclonal antibody (anti-4-1BB mAb) with intra-tumoral adenoviral-mediated gene transfer of the 4-1BB ligand (ADV/4-1BBL) to liver metastases in a syngeneic, animal model of breast cancer. Both treatments induced a dramatic regression of pre-established tumor. When combined with intra-tumoral delivery of the IL-12 gene. both anti-4-1BB mAb and ADV/4-1BBL were synergistic and led to survival rates of 87% and 78%, respectively, The anti-tumor immunity is mainly mediated by CD4(+) T cells in IL-12 plus 4-1BB ligand-treated animals, and CD8(-) T cells in IL-12 plus anti-4-1BB mAb-treated animals. However, only long-term survivors after treatment with IL-12 and 4-1BBL genes have showed significantly potent, systemic, and tumor-specific T cell-mediated immunity.
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