Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine - PubMed (original) (raw)

Clinical Trial

doi: 10.1007/s00262-009-0811-7. Epub 2009 Dec 31.

Paul Lorigan, Ulrich Keilholz, Dirk Schadendorf, Adrian Harris, Christian Ottensmeier, John Smyth, Klaus Hoffmann, Richard Anderson, Martin Cripps, Joerg Schneider, Robert Hawkins

Affiliations

Clinical Trial

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

Adam Dangoor et al. Cancer Immunol Immunother. 2010 Jun.

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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Figures

Fig. 1

Fig. 1

Melan-A tetramer assay profiles for individual patients treated with higher dose regimens. a Group 5: two 2 mg DNA.Mel3 + two 1 × 109 pfu MVA.Mel3, b Group 7: one 4 mg DNA.Mel3 + two 1 × 109 pfu MVA.Mel3, and c Group 6: four 1 × 109 pfu MVA.Mel3. Immunisations at 3-week intervals. Dotted line signifies mean + 2 standard deviations (SD) of baseline response (above line positive response). open triangles administration of DNA.Mel3, closed triangles MVA.Mel3

Fig. 2

Fig. 2

T cell immune responses elicited against multiple melanoma epitopes in Patient #47. a Mean Melan-A specific response detected by tetramer assay (circles) and ELISPOT assay (squares) ± 1 SD, b Response against epitopes other than Melan-A detected by ELISPOT assay. Dotted line mean +2 SD of baseline response in the tetramer assay, dashed line mean +3 SD of the negative control responses in the ELISPOT assay, open triangles priming immunisations with 2 mg pSG2.Mel3, closed triangles boosting immunisations with 5 × 108 pfu MVA.Mel3

Fig. 3

Fig. 3

Enhanced Melan-A specific T cell responses elicited in Patient #33 after extended boosting with MVA.Mel3. Mean Melan-A specific response detected by tetramer assay (circles) and ELISPOT assay (squares) ±1 SD. T cell immune responses were not detected against other epitopes (data not shown). Initial prime with two 2 mg pSG.Mel3 (open triangles) and boost with two 1 × 107 pfu MVA.Mel3 (solid triangles). Two additional boosters of a higher dose 2 × 108 pfu MVA.Mel3 on weeks 18 and 25 (large solid triangles)

Fig. 4

Fig. 4

Kaplan-Meier survival curves showing Melan-A tetramer responders compared to non-responders. a Per protocol analysis of time-to-progression (TTP) for stage III and IV patients (29 subjects) receiving prime-boost regime (Groups 1–5 and 7), b Intention to treat analysis of survival for stage III and IV patients (31 subjects) receiving prime-boost regime (Groups 1–5 and 7). Open circles censored patients

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