Vaccination of patients with cutaneous melanoma with telomerase-specific peptides

  • Robert E. Hunger
  • Kristin Kernland Lang
  • Carrie J. Markowski
  • Sissel Trachsel
  • Mona Møller
  • Jon A. Eriksen
  • Anne-Marie Rasmussen
  • Lasse R. Braathen
  • Gustav Gaudernack
Original article



A phase I study was conducted to investigate the safety, tolerability, and immunological responses to vaccination with a combination of telomerase-derived peptides GV1001 (hTERT: 611–626) and p540 (hTERT: 540–548) using granulocyte–macrophage colony-stimulating factor (GM-CSF) or tuberculin as adjuvant in patients with cutaneous melanoma.

Experimental design

Ten patients with melanoma stages UICC IIb-IV were vaccinated 8 times intradermally with either 60 or 300 nmole of GV1001 and p540 peptide using GM-CSF as adjuvant. A second group of patients received only 300 nmole GV1001 in combination with tuberculin PPD23 injections. HLA typing was not used as an inclusion criterion. Peptide-specific immune responses were measured by delayed-type hypersensitivity (DTH) reactions, in vitro T cell proliferation assays, and cytotoxicity (51-Chromium release) assays for a selected number of clones subsequently generated.


Vaccination was well tolerated in all patients. Peptide-specific immune response measured by DTH reactions and in vitro response could be induced in a dose-dependent fashion in 7 of 10 patients. Cloned T cells from the vaccinated patients showed proliferative responses against both vaccine peptides GV1001 and p540. Furthermore, T cell clones were able to specifically lyse p540-pulsed T2 target cells and various pulsed and unpulsed tumor cell lines.


These results demonstrate that immunity to hTERT can be generated safely and effectively in patients with advanced melanoma and therefore encourage further trials.


hTERT Telomerase Melanoma Cytotoxic T cells Vaccination Immunotherapy 



This work was supported by Norsk Hydro and Berner Krebsliga (Bernese Cancer Society).


  1. 1.
    Miller AJ, Mihm MC Jr (2006) Melanoma. N Engl J Med 355:51–65PubMedCrossRefGoogle Scholar
  2. 2.
    Curiel-Lewandrowski C, Demierre MF (2000) Advances in specific immunotherapy of malignant melanoma. J Am Acad Dermatol 43:167–185; quiz 186–168Google Scholar
  3. 3.
    Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Soreide O, Eriksen JA, Moller M, Baksaas I, Lothe RA, Saeterdal I, Gaudernack G (2001) Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer 92:441–450PubMedCrossRefGoogle Scholar
  4. 4.
    Hunger RE, Brand CU, Streit M, Eriksen JA, Gjertsen MK, Saeterdal I, Braathen LR, Gaudernack G (2001) Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant. Exp Dermatol 10:161–167PubMedCrossRefGoogle Scholar
  5. 5.
    Lienard D, Rimoldi D, Marchand M, Dietrich PY, van Baren N, Geldhof C, Batard P, Guillaume P, Ayyoub M, Pittet MJ, Zippelius A, Fleischhauer K, Lejeune F, Cerottini JC, Romero P, Speiser DE (2004) Ex vivo detectable activation of Melan-A-specific T cells correlating with inflammatory skin reactions in melanoma patients vaccinated with peptides in IFA. Cancer Immun 4:4PubMedGoogle Scholar
  6. 6.
    Peterson AC, Harlin H, Gajewski TF (2003) Immunization with Melan-A peptide-pulsed peripheral blood mononuclear cells plus recombinant human interleukin-12 induces clinical activity and T cell responses in advanced melanoma. J Clin Oncol 21:2342–2348PubMedCrossRefGoogle Scholar
  7. 7.
    Slingluff CL Jr, Petroni GR, Yamshchikov GV, Barnd DL, Eastham S, Galavotti H, Patterson JW, Deacon DH, Hibbitts S, Teates D, Neese PY, Grosh WW, Chianese-Bullock KA, Woodson EM, Wiernasz CJ, Merrill P, Gibson J, Ross M, Engelhard VH (2003) Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol 21:4016–4026PubMedCrossRefGoogle Scholar
  8. 8.
    Kyte JA, Trachsel S, Risberg B, Thor Straten P, Lislerud K, Gaudernack G (2009) Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunol Immunother 58:1609–1626PubMedCrossRefGoogle Scholar
  9. 9.
    Nagorsen D, Thiel E (2006) Clinical and immunologic responses to active specific cancer vaccines in human colorectal cancer. Clin Cancer Res 12:3064–3069PubMedCrossRefGoogle Scholar
  10. 10.
    Eggermont AM (2009) Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer 45:2087–2090PubMedCrossRefGoogle Scholar
  11. 11.
    Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, Buanes T, Gaudernack G (2006) Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer 95:1474–1482PubMedCrossRefGoogle Scholar
  12. 12.
    Brunsvig PF, Aamdal S, Gjertsen MK, Kvalheim G, Markowski-Grimsrud CJ, Sve I, Dyrhaug M, Trachsel S, Moller M, Eriksen JA, Gaudernack G (2006) Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother 55:1553–1564PubMedCrossRefGoogle Scholar
  13. 13.
    Domchek SM, Recio A, Mick R, Clark CE, Carpenter EL, Fox KR, DeMichele A, Schuchter LM, Leibowitz MS, Wexler MH, Vance BA, Beatty GL, Veloso E, Feldman MD, Vonderheide RH (2007) Telomerase-specific T-cell immunity in breast cancer: effect of vaccination on tumor immunosurveillance. Cancer Res 67:10546–10555PubMedCrossRefGoogle Scholar
  14. 14.
    Greten TF, Forner A, Korangy F, N’Kontchou G, Barget N, Ayuso C, Ormandy LA, Manns MP, Beaugrand M, Bruix J (2010) A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer 10:209Google Scholar
  15. 15.
    Grabbe S, Beissert S, Schwarz T, Granstein RD (1995) Dendritic cells as initiators of tumor immune responses: a possible strategy for tumor immunotherapy? Immunol Today 16:117–121PubMedCrossRefGoogle Scholar
  16. 16.
    Vonderheide RH, Hahn WC, Schultze JL, Nadler LM (1999) The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity 10:673–679PubMedCrossRefGoogle Scholar
  17. 17.
    Gjertsen MK, Saeterdal I, Saeboe-Larssen S, Gaudernack G (2003) HLA-A3 restricted mutant ras specific cytotoxic T-lymphocytes induced by vaccination with T-helper epitopes. J Mol Med 81:43–50PubMedGoogle Scholar
  18. 18.
    Ayello J, van de Ven C, Cairo E, Hochberg J, Baxi L, Satwani P, Cairo MS (2009) Characterization of natural killer and natural killer-like T cells derived from ex vivo expanded and activated cord blood mononuclear cells: implications for adoptive cellular immunotherapy. Exp Hematol 37:1216–1229PubMedCrossRefGoogle Scholar
  19. 19.
    Brunsvig PF, Aamdal S, Gjertsen MK, Kvalheim G, Markowski-Grimsrud CJ, Sve I, Dyrhaug M, Trachsel S, Moller M, Eriksen JA, Gaudernack G (2006) Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother 55:1553–1564PubMedCrossRefGoogle Scholar
  20. 20.
    Speiser DE, Baumgaertner P, Barbey C, Rubio-Godoy V, Moulin A, Corthesy P, Devevre E, Dietrich PY, Rimoldi D, Lienard D, Cerottini JC, Romero P, Rufer N (2006) A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination. J Immunol 177:1338–1348PubMedGoogle Scholar
  21. 21.
    Speiser DE, Kyburz D, Stubi U, Hengartner H, Zinkernagel RM (1992) Discrepancy between in vitro measurable and in vivo virus neutralizing cytotoxic T cell reactivities. Low T cell receptor specificity and avidity sufficient for in vitro proliferation or cytotoxicity to peptide-coated target cells but not for in vivo protection. J Immunol 149:972–980PubMedGoogle Scholar
  22. 22.
    Schmid DA, Irving MB, Posevitz V, Hebeisen M, Posevitz-Fejfar A, Sarria JC, Gomez-Eerland R, Thome M, Schumacher TN, Romero P, Speiser DE, Zoete V, Michielin O, Rufer N (2010) Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol 184:4936–4946Google Scholar
  23. 23.
    Britten CM, Meyer RG, Frankenberg N, Huber C, Wolfel T (2004) The use of clonal mRNA as an antigenic format for the detection of antigen-specific T lymphocytes in IFN-gamma ELISPOT assays. J Immunol Method 287:125–136CrossRefGoogle Scholar
  24. 24.
    Herr W, Schneider J, Lohse AW, Meyer zum Buschenfelde KH, Wolfel T (1996) Detection and quantification of blood-derived CD8+ T lymphocytes secreting tumor necrosis factor alpha in response to HLA-A2.1-binding melanoma and viral peptide antigens. J Immunol Method 191:131–142CrossRefGoogle Scholar
  25. 25.
    Lopez M, Aguilera R, Perez C, Mendoza-Naranjo A, Pereda C, Ramirez M, Ferrada C, Aguillon JC, Salazar-Onfray F (2006) The role of regulatory T lymphocytes in the induced immune response mediated by biological vaccines. Immunobiology 211:127–136PubMedCrossRefGoogle Scholar
  26. 26.
    Markovic SN, Suman VJ, Ingle JN, Kaur JS, Pitot HC, Loprinzi CL, Rao RD, Creagan ET, Pittelkow MR, Allred JB, Nevala WK, Celis E (2006) Peptide vaccination of patients with metastatic melanoma: improved clinical outcome in patients demonstrating effective immunization. Am J Clin Oncol 29:352–360PubMedCrossRefGoogle Scholar
  27. 27.
    Quezada SA, Peggs KS, Curran MA, Allison JP (2006) CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116:1935–1945PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Robert E. Hunger
    • 1
  • Kristin Kernland Lang
    • 1
  • Carrie J. Markowski
    • 2
  • Sissel Trachsel
    • 2
  • Mona Møller
    • 3
  • Jon A. Eriksen
    • 3
  • Anne-Marie Rasmussen
    • 2
  • Lasse R. Braathen
    • 1
  • Gustav Gaudernack
    • 2
  1. 1.Department of DermatologyUniversity of Berne, InselspitalBerneSwitzerland
  2. 2.Section for Immunotherapy, Department of ImmunologyOslo University Hospital-Radiumhospitalet and University of OsloOsloNorway
  3. 3.PorsgrunnNorway

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