Cancer Immunology, Immunotherapy

, Volume 59, Issue 6, pp 863–873

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

Authors

    • Bristol Haematology and Oncology Centre
  • Paul Lorigan
    • Department of Medical OncologyChristie Hospital
  • Ulrich Keilholz
    • Department of Medicine IIICharité Hospital
  • Dirk Schadendorf
    • Skin Cancer UnitGerman Cancer Research Centre and University Hospital
  • Adrian Harris
    • Cancer Research UK Department of Medical OncologyChurchill Hospital
  • Christian Ottensmeier
    • Cancer Sciences Division, School of MedicineUniversity of Southampton
  • John Smyth
    • Edinburgh Cancer Research Centre
  • Klaus Hoffmann
    • Department of Dermatology and AllergologyRuhr-University Bochum
  • Richard Anderson
    • Oxxon Therapeutics Ltd (now Oxford Biomedica UK Ltd)
  • Martin Cripps
    • Oxxon Therapeutics Ltd (now Oxford Biomedica UK Ltd)
  • Joerg Schneider
    • Oxxon Therapeutics Ltd (now Oxford Biomedica UK Ltd)
    • Emergent BioSolutionsEmergent Product Development UK Limited
  • Robert Hawkins
    • Department of Medical OncologyChristie Hospital
Original Article

DOI: 10.1007/s00262-009-0811-7

Cite this article as:
Dangoor, A., Lorigan, P., Keilholz, U. et al. Cancer Immunol Immunother (2010) 59: 863. doi:10.1007/s00262-009-0811-7

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-γ 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.

Keywords

PrimeboostTherapeutic vaccineMelanomaPolyepitope

Copyright information

© Springer-Verlag 2009