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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 Therapy volume 9, pages 786–792 (2002)Cite this article

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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Authors and Affiliations

  1. Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY, USA

    O Martinet, Y Zang, Y Gan, P-Y Pan & S-H Chen

  2. Department of Surgery, Mount Sinai School of Medicine, New York, NY, USA

    O Martinet & CM Divino

  3. Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA

    S Thung

  4. Department of Biomathematical Sciences, Mount Sinai School of Medicine, New York, NY, USA

    J Mandeli

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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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