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

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.

• Authors: O Martinet, C M Divino, Y Zang, Y Gan, J Mandeli, S Thung, P-Y Pan, S-H Chen
• Journal: Gene therapy (Gene Ther) Vol. 9 Issue 12 Pg. 786-92 (Jun 2002) ISSN: 0969-7128 [Print] England
• PMID: 12040460 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Receptors, Nerve Growth Factor
• Receptors, Tumor Necrosis Factor
• Tnfrsf9 protein, mouse
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Interleukin-12

Topics

• Adenoviridae (genetics)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antigens, CD
• Breast Neoplasms (immunology, therapy)
• Combined Modality Therapy
• Female
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage, genetics)
• Immunity, Cellular
• Immunotherapy (methods)
• Injections, Intralesional
• Interleukin-12 (administration & dosage)
• Liver Neoplasms (immunology, secondary, therapy)
• Lymphocyte Activation
• Mice
• Mice, Inbred BALB C
• Receptors, Nerve Growth Factor (immunology)
• Receptors, Tumor Necrosis Factor (genetics, immunology)
• T-Lymphocytes (immunology)
• Tumor Necrosis Factor Receptor Superfamily, Member 9