title: Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases.
abstract: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases.
  
  
  
  Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression.
  
  
  
  Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Ileana S
authors: IS
authors: Mauldin
authors: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors: Nolan A
authors: NA
authors: Wages
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Anne M
authors: AM
authors: Stowman
authors: Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors: Ena
authors: E
authors: Wang
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Walter C
authors: WC
authors: Olson
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Donna H
authors: DH
authors: Deacon
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Kelly T
authors: KT
authors: Smith
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Nadedja
authors: N
authors: Galeassi
authors: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
authors: Jessica E
authors: JE
authors: Teague
authors: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors: Mark E
authors: ME
authors: Smolkin
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Kimberly A
authors: KA
authors: Chianese-Bullock
authors: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
authors: Rachael A
authors: RA
authors: Clark
authors: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors: Gina R
authors: GR
authors: Petroni
authors: Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors: Francesco M
authors: FM
authors: Marincola
authors: Department of Microbiology and Immunology, Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors: David W
authors: DW
authors: Mullins
authors: Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA. cls8h@virginia.edu.
authors: Craig L
authors: CL
authors: Slingluff
mesh_terms: D000287:Administration, Topical; D000368:Aged; D000634:Aminoquinolines / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D000077271:Imiquimod; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000276:immunology*; D012878:Skin Neoplasms / Q000556:secondary / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists; D059467:Transcriptome / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000634:Aminoquinolines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D016207:Cytokines; D010446:Peptide Fragments; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D022223:Vaccines, Subunit; D000077271:Imiquimod
keywords: Cytotoxic T lymphocytes; Human; Immunotherapy; Melanoma; TLR agonists; Tumor vaccines