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Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine

Research output: Contribution to journalArticle

  • Adam Dangoor
  • Paul Lorigan
  • Ulrich Keilholz
  • Dirk Schadendorf
  • Adrian Harris
  • Christian Ottensmeier
  • John Smyth
  • Klaus Hoffmann
  • Richard Anderson
  • Martin Cripps
  • Joerg Schneider
  • Robert Hawkins

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)863-873
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume59
Issue number6
DOIs
Publication statusPublished - Jun 2010

Abstract

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.

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.

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.

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.

ID: 2618438