Cancer Immunology, Immunotherapy

, Volume 59, Issue 6, pp 863–873

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

  • Adam Dangoor
  • Paul Lorigan
  • Ulrich Keilholz
  • Dirk Schadendorf
  • Adrian Harris
  • Christian Ottensmeier
  • John Smyth
  • Klaus Hoffmann
  • Richard Anderson
  • Martin Cripps
  • Joerg Schneider
  • Robert Hawkins
Original Article
  • 202 Downloads

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-γ 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.

Keywords

Primeboost Therapeutic vaccine Melanoma Polyepitope 

References

  1. 1.
    King M, Spooner D, Rowlands DC (2001) Spontaneous regression of metastatic malignant melanoma of the parotid gland and neck lymph nodes: a case report and a review of the literature. Clin Oncol (R Coll Radiol) 13:466–469Google Scholar
  2. 2.
    Itoh K, Platsoucas CD, Balch CM (1988) Autologous tumor-specific cytotoxic T lymphocytes in the infiltrate of human metastatic melanomas: activation by interleukin 2 and autologous tumor cells, and involvement of the T cell receptor. J Exp Med 168:1419–1441CrossRefPubMedGoogle Scholar
  3. 3.
    Schwartzentruber DJ, Topalian SL, Mancini M, Rosenberg SA (1991) Specific release of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IFN-gamma by human tumor-infiltrating lymphocytes after autologous tumor stimulation. J Immunol 146:3674–3681PubMedGoogle Scholar
  4. 4.
    Talebi T, Weber JS (2003) Peptide vaccine trials for melanoma: preclinical background and clinical results. Semin Cancer Biol 13:431–438CrossRefPubMedGoogle Scholar
  5. 5.
    Pilla L, Valenti R, Marrari A, Patuzzo R, Santinami M et al (2006) Vaccination: role in metastatic melanoma. Expert Rev Anticancer Ther 6:1305–1318CrossRefPubMedGoogle Scholar
  6. 6.
    Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915CrossRefPubMedGoogle Scholar
  7. 7.
    Rosenberg SA, Yang JC, Sherry RM, Hwu P, Topalian SL et al (2003) Inability to immunize patients with metastatic melanoma using plasmid DNA encoding the gp100 melanoma-melanocyte antigen. Hum Gene Ther 14:709–714CrossRefPubMedGoogle Scholar
  8. 8.
    Triozzi PL, Aldrich W, Allen KO, Carlisle RR, LoBuglio AF et al (2005) Phase I study of a plasmid DNA vaccine encoding MART-1 in patients with resected melanoma at risk for relapse. J Immunother 28:382–388CrossRefPubMedGoogle Scholar
  9. 9.
    Zhu J, Martinez J, Huang X, Yang Y (2007) Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-beta. Blood 109:619–625CrossRefPubMedGoogle Scholar
  10. 10.
    Smith CL, Dunbar PR, Mirza F, Palmowski MJ, Shepherd D et al (2005) Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence. Int J Cancer 113:259–266CrossRefPubMedGoogle Scholar
  11. 11.
    McConkey SJ, Reece WH, Moorthy VS, Webster D, Dunachie S et al (2003) Enhanced T cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat Med 9:729–735CrossRefPubMedGoogle Scholar
  12. 12.
    Palmowski MJ, Choi EM, Hermans IF, Gilbert SC, Chen JL et al (2002) Competition between CTL narrows the immune response induced by prime-boost vaccination protocols. J Immunol 168:4391–4398PubMedGoogle Scholar
  13. 13.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS et al (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  14. 14.
    Xu Y, Theobald V, Sung C, DePalma K, Atwater L et al (2008) Validation of a HLA-A2 tetramer flow cytometric method, IFNgamma real time RT-PCR, and IFNgamma ELISPOT for detection of immunologic response to gp100 and MelanA/MART-1 in melanoma patients. J Transl Med 6:61CrossRefPubMedGoogle Scholar
  15. 15.
    Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N et al (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMedGoogle Scholar
  16. 16.
    Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS et al (2001) Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634PubMedGoogle Scholar
  17. 17.
    Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M et al (2006) Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 24:4738–4745 Epub 2006 Sep 4711CrossRefPubMedGoogle Scholar
  18. 18.
    Vaishampayan U, Abrams J, Darrah D, Jones V, Mitchell MS (2002) Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clin Cancer Res 8:3696–3701PubMedGoogle Scholar
  19. 19.
    Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA et al (2005) Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675, 206. J Clin Oncol 23:8968–8977 Epub 2005 Oct 8963CrossRefPubMedGoogle Scholar
  20. 20.
    Hoos A, Parmiani G, Hege K, Sznol M, Loibner H et al (2007) A clinical development paradigm for cancer vaccines and related biologics. J Immunother 30:1–15CrossRefPubMedGoogle Scholar
  21. 21.
    Schneider J, Gilbert SC, Blanchard TJ, Hanke T, Robson KJ et al (1998) Enhanced immunogenicity for CD8+ T cell induction and complete protective efficacy of malaria DNA vaccination by boosting with modified vaccinia virus Ankara. Nat Med 4:397–402CrossRefPubMedGoogle Scholar
  22. 22.
    Harrop R, Connolly N, Redchenko I, Valle J, Saunders M et al (2006) Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clin Cancer Res 12:3416–3424CrossRefPubMedGoogle Scholar
  23. 23.
    Luescher IF, Romero P, Kuznetsov D, Rimoldi D, Coulie P et al (1996) HLA photoaffinity labeling reveals overlapping binding of homologous melanoma-associated gene peptides by HLA-A1, HLA-A29, and HLA-B44. J Biol Chem 271:12463–12471CrossRefPubMedGoogle Scholar
  24. 24.
    Harrer E, Bauerle M, Ferstl B, Chaplin P, Petzold B et al (2005) Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption. Antivir Ther 10:285–300PubMedGoogle Scholar
  25. 25.
    Wang F, Bade E, Kuniyoshi C, Spears L, Jeffery G et al (1999) Phase I trial of a MART-1 peptide vaccine with incomplete Freund’s adjuvant for resected high-risk melanoma. Clin Cancer Res 5:2756–2765PubMedGoogle Scholar
  26. 26.
    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 21:2342–2348CrossRefPubMedGoogle Scholar
  27. 27.
    Benlalam H, Vignard V, Khammari A, Bonnin A, Godet Y et al (2007) Infusion of Melan-A/Mart-1 specific tumor-infiltrating lymphocytes enhanced relapse-free survival of melanoma patients. Cancer Immunol Immunother 56:515–526CrossRefPubMedGoogle Scholar
  28. 28.
    Mackensen A, Meidenbauer N, Vogl S, Laumer M, Berger J et al (2006) Phase I study of adoptive T cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. J Clin Oncol 24:5060–5069CrossRefPubMedGoogle Scholar
  29. 29.
    Luckay A, Sidhu MK, Kjeken R, Megati S, Chong SY et al (2007) Effect of plasmid DNA vaccine design and in vivo electroporation on the resulting vaccine-specific immune responses in rhesus macaques. J Virol 81:5257–5269CrossRefPubMedGoogle Scholar
  30. 30.
    Appay V, Voelter V, Rufer N, Reynard S, Jandus C et al (2007) Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma. J Immunother 30:240–250CrossRefPubMedGoogle Scholar
  31. 31.
    Emens LA, Jaffee EM (2005) Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res 65:8059–8064CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Adam Dangoor
    • 1
  • Paul Lorigan
    • 2
  • Ulrich Keilholz
    • 3
  • Dirk Schadendorf
    • 4
  • Adrian Harris
    • 5
  • Christian Ottensmeier
    • 6
  • John Smyth
    • 7
  • Klaus Hoffmann
    • 8
  • Richard Anderson
    • 9
  • Martin Cripps
    • 9
  • Joerg Schneider
    • 9
    • 10
  • Robert Hawkins
    • 2
  1. 1.Bristol Haematology and Oncology CentreBristolUK
  2. 2.Department of Medical OncologyChristie HospitalManchesterUK
  3. 3.Department of Medicine IIICharité HospitalBerlinGermany
  4. 4.Skin Cancer UnitGerman Cancer Research Centre and University HospitalMannheimGermany
  5. 5.Cancer Research UK Department of Medical OncologyChurchill HospitalOxfordUK
  6. 6.Cancer Sciences Division, School of MedicineUniversity of SouthamptonSouthamptonUK
  7. 7.Edinburgh Cancer Research CentreEdinburghUK
  8. 8.Department of Dermatology and AllergologyRuhr-University BochumBochumGermany
  9. 9.Oxxon Therapeutics Ltd (now Oxford Biomedica UK Ltd)OxfordUK
  10. 10.Emergent BioSolutionsEmergent Product Development UK LimitedWokinghamUK

Personalised recommendations