title: Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting.
abstract: BACKGROUND
  Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting.
  
  
  METHODS
  Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m(2) to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines.
  
  
  RESULTS
  Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting.
  
  
  CONCLUSIONS
  Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents.
  
  
  BACKGROUND
  NCT01435499.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans Street, Room 507, Baltimore, MD, 21287, USA. evanlipson@jhmi.edu.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Lipson
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. sharfwi@jhmi.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Sharfman
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. shuming1@jhu.edu.
authors.forename: Shuming
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. tmcmill3@jhmi.edu.
authors.forename: Tracee L
authors.initials: TL
authors.lastname: McMiller
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. tsalay1@jhmi.edu.
authors.forename: Theresa S
authors.initials: TS
authors.lastname: Pritchard
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jansalas@gmail.com.
authors.forename: January T
authors.initials: JT
authors.lastname: Salas
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. sartosu@jhmi.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Sartorius-Mergenthaler
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. ifreed@jhmi.edu.
authors.forename: Irwin
authors.initials: I
authors.lastname: Freed
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. sravi2@jhmi.edu.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Ravi
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. hwang76@jhmi.edu.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. bluber1@jhmi.edu.
authors.forename: Brandon
authors.initials: B
authors.lastname: Luber
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. davisja@jhmi.edu.
authors.forename: Janice Davis
authors.initials: JD
authors.lastname: Sproul
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jtaube1@jhmi.edu.|Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jtaube1@jhmi.edu.
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. dpardol1@jhmi.edu.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. stopali1@jhmi.edu.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D019496:Cancer Vaccines / Q000276:immunology*; D002452:Cell Count; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007109:Immunity / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000097:blood / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000276:immunology; D011859:Radiography; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D019496:Cancer Vaccines; C000593794:GVAX vaccine; D010455:Peptides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide