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

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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.

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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

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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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Authors and Affiliations

  1. III. Medizinische Klinik, Johannes Gutenberg-Universitaet, Langenbeckstrasse 1, 55116, Mainz, Germany

    Ralf G. Meyer, Cedrik M. Britten, Ulrike Siepmann, Christoph Huber & Thomas Wölfel

  2. Institut fuer Pathologie, Johannes Gutenberg-Universitaet, Mainz, Germany

    Tolga A. Sagban & Hans A. Lehr

  3. Institut fuer Immunologie, Technische Universitaet, Dresden, Germany

    Bernd Weigle & Marc Schmitz

  4. Bavarian Nordic GmbH, Martinsried, Germany

    Barbara Petzold, Luis Mateo, Nathaly Arndtz & Paul Chaplin

  5. III. Medizinische Klinik, Technische Universitaet, Munich, Germany

    Burkhard Schmidt & Helga Bernhard

  6. Klinische Kooperationsgruppe Umweltdermatologie und Allergologie GSF/TUM, Klinik und Poliklinik fuer Dermatologie und Allergologie, Technische Universitaet Muenchen, Munich, Germany

    Thilo Jakob

  7. Klinik und Poliklinik fuer Dermatologie und Allergologie, Technische Universitaet Muenchen, Munich, Germany

    Rüdiger Hein

  8. Dermatologische Universitaetsklinik, Erlangen, Germany

    Gerold Schuler & Beatrice Schuler-Thurner

  9. Klinik fuer Dermatologie, Universitaet Essen, Essen, Germany

    Stephan N. Wagner

  10. GSF, Institut fuer Molekulare Virologie, Munich, Germany

    Ingo Drexler & Gerd Sutter

  11. HSK-Aukammallee, Wilhelm Fresenius Klinik, Wiesbaden, Germany

    Jost Metz

  12. Hautklinik, Johannes Gutenberg-Universitaet, Mainz, Germany

    Alexander Enk

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  1. Ralf G. Meyer
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Correspondence to Thomas Wölfel.

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Meyer, R.G., Britten, C.M., Siepmann, U. et al. A phase I vaccination study with tyrosinase in patients with stage II melanoma using recombinant modified vaccinia virus Ankara (MVA-hTyr). Cancer Immunol Immunother 54, 453–467 (2005). https://doi.org/10.1007/s00262-004-0616-7

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