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- Title
T cell actication with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer.
- Authors
Martinet, O.; Divino, C.M.; Zang, Y.; Gan, Y.; Mandeli, J.; Thung, S.; Pan, P.-Y.; Chen, S.-H.
- 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 antitumor response. Ligation of 4-1BB, a co-stimulatory receptor expressed on activated T cells, is known to amplify T cellmediated 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 adenoviralmediated gene transfer of the 4-1BB /igand (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/41BBL were synergistic and led to survival rates of 87% and 78%, respectively. The anti-tumor immunity is mainly mediated by CD4[sup +] T cells in IL-12 plus 4-1BB ligand-treated animals, and CD8[sup +] T cells in IL-12 plus anti-4-1BB mAbtreated animals. However, only long-term survivors after treatment with IL-12 and 4-1BBL genes have showed significantly potent, systemic, and tumor-specific T cellmediated immunity.
- Subjects
INTERLEUKIN-12; LIVER metastasis; BREAST cancer gene therapy
- Publication
Gene Therapy, 2002, Vol 9, Issue 12, p786
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3301687