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dc.contributor.authorDangoor, A
dc.contributor.authorLorigan, Paul C
dc.contributor.authorKeilholz, U
dc.contributor.authorSchadendorf, D
dc.contributor.authorHarris, A
dc.contributor.authorOttensmeier, C
dc.contributor.authorSmyth, J
dc.contributor.authorHoffmann, K
dc.contributor.authorAnderson, R
dc.contributor.authorCripps, M
dc.contributor.authorSchneider, J
dc.contributor.authorHawkins, Robert E
dc.date.accessioned2010-08-10T12:48:33Z
dc.date.available2010-08-10T12:48:33Z
dc.date.issued2010-06
dc.identifier.citationClinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. 2010, 59 (6):863-73 Cancer Immunol Immunotheren
dc.identifier.issn1432-0851
dc.identifier.pmid20043222
dc.identifier.doi10.1007/s00262-009-0811-7
dc.identifier.urihttp://hdl.handle.net/10541/109384
dc.description.abstractBACKGROUND: 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.
dc.language.isoenen
dc.subjectCancer Antigensen
dc.subjectCancer Metastasisen
dc.subjectCancer Proteinsen
dc.subjectCancer Stagingen
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAntigens, Neoplasm
dc.subject.meshCD8-Positive T-Lymphocytes
dc.subject.meshCancer Vaccines
dc.subject.meshDisease Progression
dc.subject.meshEpitopes, T-Lymphocyte
dc.subject.meshFemale
dc.subject.meshHLA-A2 Antigen
dc.subject.meshHumans
dc.subject.meshImmunization, Secondary
dc.subject.meshInterferon-gamma
dc.subject.meshLymphocyte Activation
dc.subject.meshMale
dc.subject.meshMelanoma
dc.subject.meshMiddle Aged
dc.subject.meshNeoplasm Metastasis
dc.subject.meshNeoplasm Proteins
dc.subject.meshNeoplasm Staging
dc.subject.meshSurvival Analysis
dc.subject.meshVaccinia virus
dc.titleClinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine.en
dc.typeArticleen
dc.contributor.departmentBristol Haematology and Oncology Centre, Horfield Rd, Bristol, BS2 8ED, UK. adamd@doctors.org.uken
dc.identifier.journalCancer Immunology, Immunotherapyen
html.description.abstractBACKGROUND: 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.


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