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

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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.

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Acknowledgments

We are indebted to the patients that participated in this trial and their families. Also to the specialist nurses and medical staff who managed the patients. The following individuals provided advice and expertise—statistics and data management: Paul Talsma and Steve Turner, Synequanon Ltd (Diss, UK); data monitoring: Constella Group Inc. (Abingdon, UK); immunomonitoring: Carmen Scheibenbogen (Charité Hospital, Berlin, Germany); The Melanoma Study Group: A. Busse; S. Ugurel; A. Thoelke; G. Mousse; J. Curran; S. Pratap; G. Pearce; K. Whale.

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Authors and Affiliations

  1. Bristol Haematology and Oncology Centre, Horfield Rd, Bristol, BS2 8ED, UK

    Adam Dangoor

  2. Department of Medical Oncology, Christie Hospital, Manchester, UK

    Paul Lorigan & Robert Hawkins

  3. Department of Medicine III, Charité Hospital, Campus Benjamin-Franklin, Berlin, Germany

    Ulrich Keilholz

  4. Skin Cancer Unit, German Cancer Research Centre and University Hospital, Mannheim, Germany

    Dirk Schadendorf

  5. Cancer Research UK Department of Medical Oncology, Churchill Hospital, Oxford, UK

    Adrian Harris

  6. Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, UK

    Christian Ottensmeier

  7. Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh, UK

    John Smyth

  8. Department of Dermatology and Allergology, Ruhr-University Bochum, Bochum, Germany

    Klaus Hoffmann

  9. Oxxon Therapeutics Ltd (now Oxford Biomedica UK Ltd), Oxford Science Park, Oxford, UK

    Richard Anderson, Martin Cripps & Joerg Schneider

  10. Emergent BioSolutions, Emergent Product Development UK Limited, Wokingham, UK

    Joerg Schneider

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  1. Adam Dangoor
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Correspondence to Adam Dangoor.

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Dangoor, A., Lorigan, P., Keilholz, U. et al. Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. Cancer Immunol Immunother 59, 863–873 (2010). https://doi.org/10.1007/s00262-009-0811-7

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  • DOI: https://doi.org/10.1007/s00262-009-0811-7

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