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

2.50
Hdl Handle:
http://hdl.handle.net/10541/109384
Title:
Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine.
Authors:
Dangoor, A; Lorigan, Paul C ( 0000-0002-8875-2164 ) ; Keilholz, U; Schadendorf, D; Harris, A; Ottensmeier, C; Smyth, J; Hoffmann, K; Anderson, R; Cripps, M; Schneider, J; Hawkins, Robert E
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.
Affiliation:
Bristol Haematology and Oncology Centre, Horfield Rd, Bristol, BS2 8ED, UK. adamd@doctors.org.uk
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
Issue Date:
Jun-2010
URI:
http://hdl.handle.net/10541/109384
DOI:
10.1007/s00262-009-0811-7
PubMed ID:
20043222
Type:
Article
Language:
en
ISSN:
1432-0851
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research; Medical Oncology

Full metadata record

DC FieldValue Language
dc.contributor.authorDangoor, Aen
dc.contributor.authorLorigan, Paul Cen
dc.contributor.authorKeilholz, Uen
dc.contributor.authorSchadendorf, Den
dc.contributor.authorHarris, Aen
dc.contributor.authorOttensmeier, Cen
dc.contributor.authorSmyth, Jen
dc.contributor.authorHoffmann, Ken
dc.contributor.authorAnderson, Ren
dc.contributor.authorCripps, Men
dc.contributor.authorSchneider, Jen
dc.contributor.authorHawkins, Robert Een
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.en
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

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.