title: 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.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
authors.forename: Devin B
authors.initials: DB
authors.lastname: Lowe
authors.forename: Aparna
authors.initials: A
authors.lastname: Rao
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000077784:Axitinib; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D019496:Cancer Vaccines; D007093:Imidazoles; D007191:Indazoles; C111390:OVA 323-339; C110366:OVA-8; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D018664:Interleukin-12; D010047:Ovalbumin; D000077784:Axitinib