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

Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine
Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine
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.
primeboost, therapeutic vaccine, melanoma, polyepitope
0340-7004
863-873
Dangoor, Adam
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Lorigan, Paul
a996ae96-91af-4ba9-8b66-be50cca03809
Keilholz, Ulrich
9fab9d63-1be7-4dce-b0a5-0c4140b01187
Schadendorf, Dirk
17cfc2cb-7515-4a9c-8660-28a5ae5d9705
Harris, Adrian
8b6f48f1-b0e7-489e-b84a-59750aaaf264
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Smyth, John
423fc5ff-ad5a-4520-b510-9c37748ca81c
Hoffman, Klaus
de6e4e61-f8ae-4012-9b4d-c847f5abed5c
Anderson, Richard
da4bdca7-6e10-4e0f-9974-aaf9eca8cf8a
Cripps, Martin
9a01156f-58e1-4e31-b654-0e252e3d2510
Schneider, Joerg
f0bfbac1-64e1-4f09-84b8-c11ae060b6db
Hawkins, Robert
b463472f-80e4-4d03-a3d2-a362d2560b63
Dangoor, Adam
0149daf8-930f-4ed1-b6d6-75b029f0dd02
Lorigan, Paul
a996ae96-91af-4ba9-8b66-be50cca03809
Keilholz, Ulrich
9fab9d63-1be7-4dce-b0a5-0c4140b01187
Schadendorf, Dirk
17cfc2cb-7515-4a9c-8660-28a5ae5d9705
Harris, Adrian
8b6f48f1-b0e7-489e-b84a-59750aaaf264
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Smyth, John
423fc5ff-ad5a-4520-b510-9c37748ca81c
Hoffman, Klaus
de6e4e61-f8ae-4012-9b4d-c847f5abed5c
Anderson, Richard
da4bdca7-6e10-4e0f-9974-aaf9eca8cf8a
Cripps, Martin
9a01156f-58e1-4e31-b654-0e252e3d2510
Schneider, Joerg
f0bfbac1-64e1-4f09-84b8-c11ae060b6db
Hawkins, Robert
b463472f-80e4-4d03-a3d2-a362d2560b63

Dangoor, Adam, Lorigan, Paul, Keilholz, Ulrich, Schadendorf, Dirk, Harris, Adrian, Ottensmeier, Christian, Smyth, John, Hoffman, Klaus, Anderson, Richard, Cripps, Martin, Schneider, Joerg and Hawkins, Robert (2010) Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. Cancer Immunology Immunotherapy, 59 (6), 863-873. (doi:10.1007/s00262-009-0811-7).

Record type: Article

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.

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More information

Published date: June 2010
Keywords: primeboost, therapeutic vaccine, melanoma, polyepitope

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Local EPrints ID: 147689
URI: http://eprints.soton.ac.uk/id/eprint/147689
ISSN: 0340-7004
PURE UUID: 8c06f187-bb54-451f-beb9-93ff55ea0e47

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Date deposited: 26 Apr 2010 11:59
Last modified: 14 Mar 2024 00:59

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Contributors

Author: Adam Dangoor
Author: Paul Lorigan
Author: Ulrich Keilholz
Author: Dirk Schadendorf
Author: Adrian Harris
Author: John Smyth
Author: Klaus Hoffman
Author: Richard Anderson
Author: Martin Cripps
Author: Joerg Schneider
Author: Robert Hawkins

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