T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer

O. Martinet, C. M. Divino, Y. Zang, Y. Gan, J. Mandeli, S. Thung, P. Y. Pan, S. H. Chen

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)786-792
Number of pages7
JournalGene Therapy
Volume9
Issue number12
DOIs
StatePublished - 2002

Keywords

  • 4-1BB
  • Co-stimulatory molecule
  • Gene therapy
  • Interleukin-12
  • Liver metastases

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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