title: Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine.
abstract: BACKGROUND
  Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens.
  
  
  METHODS
  Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-gamma ELISPOT assays. Safety and clinical responses were monitored.
  
  
  RESULTS
  Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions.
  
  
  CONCLUSIONS
  DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation.
authors.affiliation: Bristol Haematology and Oncology Centre, Horfield Rd, Bristol, BS2 8ED, UK. adamd@doctors.org.uk
authors.forename: Adam
authors.initials: A
authors.lastname: Dangoor
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Adrian
authors.initials: A
authors.lastname: Harris
authors.forename: Christian
authors.initials: C
authors.lastname: Ottensmeier
authors.forename: John
authors.initials: J
authors.lastname: Smyth
authors.forename: Klaus
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Richard
authors.initials: R
authors.lastname: Anderson
authors.forename: Martin
authors.initials: M
authors.lastname: Cripps
authors.forename: Joerg
authors.initials: J
authors.lastname: Schneider
authors.forename: Robert
authors.initials: R
authors.lastname: Hawkins
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009367:Neoplasm Staging; D016019:Survival Analysis; D014616:Vaccinia virus / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D007371:Interferon-gamma