title: Prolonged repeated vaccine immuno-chemotherapy induces long-term clinical responses and survival for advanced metastatic melanoma.
abstract: BACKGROUND
  Repetitive long-term Vaccinia Melanoma Cell Lysate (VMCL) vaccination schedules have proved clinically effective in producing Complete Responses and strong durable survivals for up to 6.1 years in a previous study of patients with advanced Stage IV and Stage IIIc melanoma. These studies were expanded to include 54 patients for further evaluation of these findings.
  
  
  METHODS
  54 patients comprising 48 Stage IV (6 M1a, 14 M1b, 28 M1c) and 6 advanced Stage III (5 IIIc; 1 IIIb) were studied using repeated intra-dermal VMCL vaccine therapy. If disease progressed, vaccine was continued together with standard chemotherapy (DTIC and/or Fotemustine). Overall survival was the primary end-point assessed, with clinical responses and toxicity recorded.
  
  
  RESULTS
  From vaccine commencement, median overall survival was 14 months, ranging from 4 to 121 months. Kaplan-Meier survival analysis demonstrated overall 1, 2 and 3-year survival estimates of 57%, 26% and 18.5% respectively, and overall 5-year survival of 15.4%. No appreciable toxicity was observed. Complete Responses (CR) occurred in 16.7% (9) and partial responses (PR) in 14.8% (8) of patients. Stable disease was noted in a further 25 patients (46.3%). No response to therapy was apparent in 12 patients (22.2%). The overall response rate was 31.5% (CR + PR), with clinically significant responses (CR + PR + SD) in 77.8% of patients. Strong, durable clinical responses with overall survivals ≥ 23 months occurred in 29.6% of patients treated with repeated VMCL vaccine for advanced melanoma, (+/- concurrent chemotherapy).
  
  
  CONCLUSIONS
  Prolonged, repetitive VMCL vaccination immunotherapy appears to be a clinically effective means of generating relatively high CR rates, useful clinical responses and long-term survivals, with little toxicity, but remains notably under-explored. Successive immunomodulation might explain the results. Closer analysis of repetitive dosing is required to improve clinical response rates and survival, perhaps by optimising the timing of immunotherapy delivery.
  
  
  BACKGROUND
  Australian and New Zealand Clinical Trials Registry ANZCTRN12605000425695.
authors.affiliation: Discipline of Surgery, University of Adelaide, Adelaide Melanoma Unit, Royal Adelaide Hospital, Adelaide, South Australia Australia.
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Coventry
authors.affiliation: Discipline of Surgery, University of Adelaide, Adelaide Melanoma Unit, Royal Adelaide Hospital, Adelaide, South Australia Australia.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Lilly
authors.affiliation: Kolling Institute University of Sydney, New South Wales, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.affiliation: Medical Oncology, North Adelaide Oncology, Calvary Hospital, North Adelaide, South Australia 5006 Australia.
authors.forename: Antonio
authors.initials: A
authors.lastname: Michele
authors.affiliation: Discipline of Surgery, University of Adelaide, Adelaide Melanoma Unit, Royal Adelaide Hospital, Adelaide, South Australia Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bright
keywords: Complete response; Immuno-Chemotherapy; Immunotherapy; Metastatic melanoma; Repetitive vaccinations; Survival; VMCL; Vaccine