Combined vaccine+axitinib therapy yields superior antitumor efficacy in a murine melanoma model.

Abstract

Axitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptors, has demonstrated modest efficacy when applied as a single agent in the setting of advanced-stage melanoma. On the basis of the reported ability of axitinib to 'normalize' the tumor vasculature, we hypothesize that combination therapy using axitinib plus specific peptide-based vaccination would promote superior activation and recruitment of protective T cells into the melanoma microenvironment, leading to enhanced treatment benefit. Using a subcutaneous M05 (B16.OVA) melanoma model, we observed that a treatment regimen consisting of a 7-day course of axitinib (0.5 mg/day provided orally) combined with a subcutaneous vaccine [ovalbumin (OVA) peptide-pulsed syngenic dendritic cells adenovirally engineered to produce IL-12p70] yielded superior protection against melanoma growth and extended overall survival when compared with animals receiving either single modality therapy. Treatment benefits were associated with: (a) a reduction in suppressor cell (myeloid-derived suppressor cells and Treg) populations in the tumor, (b) activation of tumor vascular endothelial cells, and (c) activation and recruitment of type-1, vaccine-induced CD8 T cells into tumors. These results support the therapeutic superiority of combined vaccine+axitinib immunotherapy and the translation of such approaches into the clinic for the treatment of patients with advanced-stage melanoma.

• Authors: Anamika Bose, Devin B Lowe, Aparna Rao, Walter J Storkus
• Journal: Melanoma research (Melanoma Res) Vol. 22 Issue 3 Pg. 236-43 (Jun 2012) ISSN: 1473-5636 [Electronic] England
• PMID: 22504156 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Cancer Vaccines
• Imidazoles
• Indazoles
• OVA 323-339
• OVA-8
• Peptide Fragments
• Protein Kinase Inhibitors
• Interleukin-12
• Ovalbumin
• Axitinib

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Axitinib
• Cancer Vaccines (immunology)
• Cell Line, Tumor
• Combined Modality Therapy
• Dendritic Cells (immunology, transplantation)
• Endothelial Cells (drug effects, immunology)
• Female
• Imidazoles (pharmacology)
• Indazoles (pharmacology)
• Interleukin-12 (biosynthesis, genetics)
• Lymphocyte Activation (drug effects)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Melanoma (blood supply, drug therapy, immunology, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Ovalbumin (immunology)
• Peptide Fragments (immunology)
• Protein Kinase Inhibitors (pharmacology)
• Skin Neoplasms (blood supply, drug therapy, immunology, pathology, therapy)
• T-Lymphocytes (drug effects, immunology)
• Time Factors
• Tumor Burden (drug effects)
• Tumor Microenvironment (drug effects)