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

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    Authors
    Dangoor, A
    Lorigan, Paul C
    Keilholz, U
    Schadendorf, D
    Harris, A
    Ottensmeier, C
    Smyth, J
    Hoffmann, K
    Anderson, R
    Cripps, M
    Schneider, J
    Hawkins, Robert E
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    Affiliation
    Bristol Haematology and Oncology Centre, Horfield Rd, Bristol, BS2 8ED, UK. adamd@doctors.org.uk
    Issue Date
    2010-06
    
    Metadata
    Show full item record
    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.
    Citation
    Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. 2010, 59 (6):863-73 Cancer Immunol Immunother
    Journal
    Cancer Immunology, Immunotherapy
    URI
    http://hdl.handle.net/10541/109384
    DOI
    10.1007/s00262-009-0811-7
    PubMed ID
    20043222
    Type
    Article
    Language
    en
    ISSN
    1432-0851
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00262-009-0811-7
    Scopus Count
    Collections
    All Christie Publications
    All Paterson Institute for Cancer Research
    Medical Oncology

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