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Cancer Immunology, Immunotherapy

, Volume 54, Issue 5, pp 453–467 | Cite as

A phase I vaccination study with tyrosinase in patients with stage II melanoma using recombinant modified vaccinia virus Ankara (MVA-hTyr)

  • Ralf G. Meyer
  • Cedrik M. Britten
  • Ulrike Siepmann
  • Barbara Petzold
  • Tolga A. Sagban
  • Hans A. Lehr
  • Bernd Weigle
  • Marc Schmitz
  • Luis Mateo
  • Burkhard Schmidt
  • Helga Bernhard
  • Thilo Jakob
  • Rüdiger Hein
  • Gerold Schuler
  • Beatrice Schuler-Thurner
  • Stephan N. Wagner
  • Ingo Drexler
  • Gerd Sutter
  • Nathaly Arndtz
  • Paul Chaplin
  • Jost Metz
  • Alexander Enk
  • Christoph Huber
  • Thomas WölfelEmail author
Original Article

Abstract

A significant percentage of patients with stage II melanomas suffer a relapse after surgery and therefore need the development of adjuvant therapies. In the study reported here, safety and immunological response were analyzed after vaccination in an adjuvant setting with recombinant modified vaccinia virus Ankara carrying the cDNA for human tyrosinase (MVA-hTyr). A total of 20 patients were included and vaccinated three times at 4-week intervals with 5×108 IU of MVA-hTyr each time. The responses to the viral vector, to known HLA class I–restricted tyrosinase peptides, and to dendritic cells transfected with tyrosinase mRNA, were investigated by ELISpot assay on both ex vivo T cells and on T cells stimulated in vitro prior to testing. The delivery of MVA-hTyr was safe and did not cause any side effects above grade 2. A strong response to the viral vector was achieved, indicated by an increase in the frequency of MVA-specific CD4+ and CD8+ T cells and an increase in virus-specific antibody titers. However, no tyrosinase-specific T-cell or antibody response was observed with MVA-hTyr in any of the vaccinated patients. Although MVA-hTyr provides a safe and effective antigen-delivery system, it does not elicit a measurable immune response to its transgene product in patients with stage II melanoma after repeated combined intradermal and subcutaneous vaccination. We presume that modification of the antigen and/or prime-boost vaccination applying different approaches to antigen delivery may be required to induce an effective tyrosinase-specific immune response.

Keywords

ELISpot Melanoma MVA Phase I Tyrosinase Vaccination 

Abbreviations

AJCC

American Joint Committee on Cancer

APC

Antigen-presenting cell

BN

Bavarian Nordic

CEF

Chicken embryo fibroblast

CTL

Cytotoxic T lymphocyte

ELISA

Enzyme-linked immunosorbent assay

ELISpot

Enzyme-linked immunosorbent spot

IFN

Interferon

IL

Interleukin

MAA

Melanoma-associated antigen

MDA

Melanosomal differentiation antigen

MVA

Modified vaccinia virus Ankara

PBMC

Peripheral blood mononuclear cell

UPN

Unique patient number

Notes

Acknowledgements

This study is an investigator-initiated study sponsored by Bavarian Nordic GmbH, Martinsried, Germany. The data management, protocol review, monitoring, and quality control was performed by Harrison Clinical Research, München, Germany. Immunological response analyses were performed at the Tumor-Vaccination Center, Mainz, Germany, that is supported by grant 70-2427-HuI from Deutsche Krebshilfe. Ralf G. Meyer was supported by grant 8312-38 62 61/439 from Stiftung Innovation Rheinland Pfalz, and T.W. was supported by a grant from Deutsche Forschungsgemeinschaft (SFB 432/A1). The technical assistance of Andrea Gstöttner and Caroline Eberhardt and the work of the study nurses Ilse El-Kholy and Patricia Meinhardt are gratefully acknowledged.

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ralf G. Meyer
    • 1
  • Cedrik M. Britten
    • 1
  • Ulrike Siepmann
    • 1
  • Barbara Petzold
    • 4
  • Tolga A. Sagban
    • 2
  • Hans A. Lehr
    • 2
  • Bernd Weigle
    • 3
  • Marc Schmitz
    • 3
  • Luis Mateo
    • 4
  • Burkhard Schmidt
    • 5
  • Helga Bernhard
    • 5
  • Thilo Jakob
    • 6
  • Rüdiger Hein
    • 7
  • Gerold Schuler
    • 8
  • Beatrice Schuler-Thurner
    • 8
  • Stephan N. Wagner
    • 9
  • Ingo Drexler
    • 10
  • Gerd Sutter
    • 10
  • Nathaly Arndtz
    • 4
  • Paul Chaplin
    • 4
  • Jost Metz
    • 11
  • Alexander Enk
    • 12
  • Christoph Huber
    • 1
  • Thomas Wölfel
    • 1
    Email author
  1. 1.III. Medizinische KlinikJohannes Gutenberg-UniversitaetMainzGermany
  2. 2.Institut fuer PathologieJohannes Gutenberg-UniversitaetMainzGermany
  3. 3.Institut fuer ImmunologieTechnische UniversitaetDresdenGermany
  4. 4.Bavarian Nordic GmbHMartinsriedGermany
  5. 5.III. Medizinische KlinikTechnische UniversitaetMunichGermany
  6. 6.Klinische Kooperationsgruppe Umweltdermatologie und Allergologie GSF/TUM, Klinik und Poliklinik fuer Dermatologie und AllergologieTechnische Universitaet MuenchenMunichGermany
  7. 7.Klinik und Poliklinik fuer Dermatologie und AllergologieTechnische Universitaet MuenchenMunichGermany
  8. 8.Dermatologische UniversitaetsklinikErlangenGermany
  9. 9.Klinik fuer DermatologieUniversitaet EssenEssenGermany
  10. 10.GSF, Institut fuer Molekulare VirologieMunichGermany
  11. 11.HSK-AukammalleeWilhelm Fresenius KlinikWiesbadenGermany
  12. 12.HautklinikJohannes Gutenberg-UniversitaetMainzGermany

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