Combined stimulation of IL-2 and 4-1BB receptors augments the antitumor activity of E7 DNA vaccines by increasing Ag-specific CTL responses.

Abstract

Human papillomavirus (HPV) infection is a major cause of cervical cancer. Here, we investigate whether concurrent therapy using HPV E7 DNA vaccines (pE7) plus IL-2 vs. IL-15 cDNA and anti-4-1BB Abs might augment antitumor activity against established tumors. IL-2 cDNA was slightly better than IL-15 cDNA as a pE7 adjuvant. Co-delivery of pE7+IL-2 cDNA increased tumor cure rates from 7% to 27%, whereas co-delivery of pE7+IL-2 cDNA with anti-4-1BB Abs increased tumor cure rates from 27% to 67% and elicited long-term memory responses. This increased activity was concomitant with increased induction of Ag-specific CTL activity and IFN-γ responses, but not with Ag-specific IgG production. Moreover, the combined stimulation of IL-2 and 4-1BB receptors with rIL-2 and anti-4-1BB Abs resulted in enhanced production of IFN-γ from Ag-specific CD8+ T cells. However, this effect was abolished by treatment with anti-IL-2 Abs and 4-1BB-Fc, suggesting that the observed effect was IL-2- and anti-4-1BB Ab-specific. A similar result was also obtained for Ag-specific CTL activity. Thus, these studies demonstrate that combined stimulation through the IL-2 and 4-1BB receptors augments the Ag-specific CD8+ CTL responses induced by pE7, increasing tumor cure rates and long-term antitumor immune memory. These findings may have implications for the design of DNA-based therapeutic vaccines against cancer.

• Authors: Ha Kim, Byungsuk Kwon, Jeong-Im Sin
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e83765 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24391824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Interleukin-15
• Interleukin-2
• Papillomavirus E7 Proteins
• Papillomavirus Vaccines
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Vaccines, DNA
• Interferon-gamma

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Humans
• Interferon-gamma (metabolism)
• Interleukin-15 (antagonists & inhibitors, immunology)
• Interleukin-2 (antagonists & inhibitors, immunology)
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (immunology, pathology, prevention & control)
• Papillomavirus E7 Proteins (immunology)
• Papillomavirus Vaccines (therapeutic use)
• Stromal Cells (metabolism)
• T-Lymphocytes, Cytotoxic (immunology)
• Tumor Cells, Cultured
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (antagonists & inhibitors, immunology)
• Vaccines, DNA (therapeutic use)