title: The impact of imiquimod, a Toll-like receptor-7 ligand (TLR7L), on the immunogenicity of melanoma peptide vaccination with adjuvant Flt3 ligand.
abstract: Dendritic cells (DCs) show promise as adjuvants in anticancer immunotherapeutic strategies. Flt3 ligand (FL) is a hematopoietic growth factor that increases the number of immature DCs in the blood and other tissues. We treated 27 patients with metastatic or high-risk resected melanoma with s.c. FL daily for 14 d in three 28 d cycles. Eighteen of these patients also received vaccination with influenza (Flu), Melan-A (Mel), tyrosinase (Tyr), and NY-ESO-1 peptides. To induce local DC maturation, 8 of the vaccinated patients had imiquimod, a Toll-like receptor-7 ligand (TLR7L), applied topically to their vaccine sites. Patients were monitored for clinical and hematological effects. Immune responses were assessed by cutaneous reactivity to vaccination and by the induction of peptide-specific CD8+ T-cells. Eight patients did not complete the protocol due to adverse events related to their cancer. The treatment was generally safe and well tolerated, although some patients developed clinically significant toxicities related to FL. FL induced increases in immature CD11c+ and CD123+ peripheral blood (PB) DCs. Other hematological effects included monocytosis, granulocytosis, and thrombocytosis, which were marked in some patients. Cutaneous reactions to peptide vaccination and circulating peptide-specific CD8+ T-cells were more frequent in imiquimod-treated patients. FL treatment of melanoma patients has pleiotropic clinical and hematological effects. In vivo maturation of FL-generated DCs using imiquimod may increase immune responses to tumor antigens.
authors.affiliation: Cancer Vaccine Laboratory, Ludwig Institute for Cancer Research, Austin Health, Studley Road, Heidelberg, 3084, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Wendie
authors.initials: W
authors.lastname: Hopkins
authors.forename: Heather
authors.initials: H
authors.lastname: Jackson
authors.forename: Nektaria
authors.initials: N
authors.lastname: Dimopoulos
authors.forename: Tsin
authors.initials: T
authors.lastname: Tai
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Chen
authors.forename: Phillip
authors.initials: P
authors.lastname: Parente
authors.forename: Michael
authors.initials: M
authors.lastname: Jefford
authors.forename: Kelly-Anne
authors.initials: KA
authors.lastname: Masterman
authors.forename: Dania
authors.initials: D
authors.lastname: Caron
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D000077271:Imiquimod; D016233:Immunotherapy, Active / Q000379:methods*; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D016207:Cytokines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; C084881:flt3 ligand protein; D014442:Monophenol Monooxygenase; D000077271:Imiquimod