Abstract
We have shown that interleukin-12 (IL-12) generated a strong, albeit transient, anti-tumor response, mostly mediated by natural killer (NK) cell. T cell participation, in addition to NK cells, was essential for persistence of the anti-tumor 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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Acknowledgements
The authors thank Dr Savio Woo, Dr Lieping Chen, Dr Bernhard Sauter and Dr Simon Hall for helpful discussion; and Gae O Decker-Garrad for editorial assistance. This work was supported in part by NCI grants CA-75175, CA-84404 and CA 70337, and Sharp Foundation to Shu-Hsia Chen, PhD; and grant 98-370GT of The Susan G Kormen Breast Cancer Foundation to Celia M Divino, MD.
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Martinet, O., Divino, C., Zang, Y. et al. T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer. Gene Ther 9, 786–792 (2002). https://doi.org/10.1038/sj.gt.3301687
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DOI: https://doi.org/10.1038/sj.gt.3301687
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