Skip to main content
SpringerLink
Log in

Adjuvant vaccination with melanoma antigen-pulsed dendritic cells in stage III melanoma patients

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Dendritic cells may be successfully used to induce in vivo-specific anti-tumor responses when combined with the appropriate antigen in the appropriate context. The purpose of this study was to evaluate efficacy of peptide-loaded DC vaccine in high-risk stage III melanoma patients after lymph node dissection (LND). HLA-A2+, -A1+, or -A3+ melanoma patients (N = 22), stage III, N1b-N3, received 5–16 (median: 11) DC vaccines loaded with MHC class-I-restricted melanoma peptides respective to the patient’s haplotype, and with autologous tumor lysate, if available. Vaccinated patients were matched to unvaccinated stage III controls (22 of 869) by sex, number of metastatic lymph nodes, extracapsular involvement, LND type, Breslow stage, and ulceration. Vaccination elicited cutaneous delayed-type hypersensitivity (DTH) or/and IFN-γ-producing CD8+ cell response to melanoma peptides in 15 of 22 patients. Three-year overall survival (OS) rate was 68.2% in the vaccinated group versus 25.7% in the control group, P value accounting for matching: 0.0290. In a Cox regression model, hazard ratio (HR) for death of vaccinated patients was 0.31 [95% confidence interval (CI): 0.10–0.94]. The corresponding values for 3-year disease-free survival rate were 40.9 versus 14.5%, P = 0.1083; HR of recurrence for vaccinated, 0.46 (95% CI: 0.18–1.22). There was no grade >1 toxicity. The DC/peptide vaccine was well tolerated and elicited immune responses to melanoma antigens. Vaccinated patients had significantly longer OS after LND than the matched controls, but a significant improvement in the primary endpoint DFS was not achieved.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mehta-Damani A, Markowicz S, Engleman EG. Generation of antigen-specific CD8+ CTLs from naive precursors. J Immunol. 1994;153:996–1003.

    PubMed  CAS  Google Scholar 

  2. Mehta-Damani A, Markowicz S, Engleman EG. Generation of antigen-specific CD4+ T cell lines from naive precursors. Eur J Immunol. 1995;25:1206–11.

    Article  PubMed  CAS  Google Scholar 

  3. Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2:52–8.

    Article  PubMed  CAS  Google Scholar 

  4. Timmerman JM, Czerwinski DK, Davis TA, et al. Idiotype pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood. 2002;99:1517–26.

    Article  PubMed  CAS  Google Scholar 

  5. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.

    Article  PubMed  CAS  Google Scholar 

  6. Nestle FO, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998;4:328–32.

    Article  PubMed  CAS  Google Scholar 

  7. Banchereau J, Palucka AK, Dhodapkar M, et al. Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell vaccine. Cancer Res. 2001;61:6451–8.

    PubMed  CAS  Google Scholar 

  8. O’Rourke MG, Johnson M, Lanagan C, et al. Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine. Cancer Immunol Immunother. 2003;52:387–95.

    PubMed  Google Scholar 

  9. O’Rourke MG, Johnson MK, Lanagan CM, et al. Dendritic cell immunotherapy for stage IV melanoma. Melanoma Res. 2007;17:316–22.

    Article  PubMed  Google Scholar 

  10. Schadendorf D, Ugurel S, Schuler-Thurner B, et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006;17:563–70.

    Article  PubMed  CAS  Google Scholar 

  11. Engell-Noerregaard L, Hansen TH, Andersen MH, Thor Straten P, Svane IM. Review of clinical studies on dendritic cell-based vaccination of patients with malignant melanoma: assessment of correlation between clinical response and vaccine parameters. Cancer Immunol Immunother. 2009;58:1–14.

    Article  PubMed  CAS  Google Scholar 

  12. Schadendorf D, Algarra SM, Bastholt L, et al. Immunotherapy of distant metastatic disease. Ann Oncol. 2009;20(Suppl 6):vi41–50.

    Article  PubMed  Google Scholar 

  13. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10:909–15.

    Article  PubMed  CAS  Google Scholar 

  14. Koos D, Josephs SF, Alexandrescu DT, et al. Tumor vaccines in 2010: need for integration. Cell Immunol. 2010;263:138–47.

    Article  PubMed  CAS  Google Scholar 

  15. Lesterhuis WJ, Aarntzen EH, De Vries IJ, et al. Dendritic cell vaccines in melanoma: from promise to proof? Crit Rev Oncol Hematol. 2008;66:118–34.

    Article  PubMed  CAS  Google Scholar 

  16. Letsch A, Keilholz U, Fluck M, et al. Peptide vaccination after repeated resection of metastases can induce a prolonged relapse-free interval in melanoma patients. Int J Cancer. 2005;114:936–41.

    Article  PubMed  CAS  Google Scholar 

  17. Tuettenberg A, Becker C, Huter E, Knop J, Enk AH, Jonuleit H. Induction of strong and persistent MelanA/MART-1-specific immune responses by adjuvant dendritic cell-based vaccination of stage II melanoma patients. Int J Cancer. 2006;118:2617–27.

    Article  PubMed  CAS  Google Scholar 

  18. Testori A, Rutkowski P, Marsden J, et al. Surgery and radiotherapy in the treatment of cutaneous melanoma. Ann Oncol. 2009;20(Suppl 6):vi22–9.

    Article  PubMed  Google Scholar 

  19. Mortarini R, Anichini A, Di Nicola M, et al. Autologous dendritic cells derived from CD34+ progenitors and from monocytes are not functionally equivalent antigen-presenting cells in the induction of MelanA/Mart-127-35-specific CTLs from peripheral blood lymphocytes of melanoma patients with low frequency of CTL precursors. Cancer Res. 1997;57:5534–41.

    PubMed  CAS  Google Scholar 

  20. Nowecki ZI, Rutkowski P, Michej W. The survival benefit to patients with positive sentinel node melanoma after completion lymph node dissection may be limited to the subgroup with a primary lesion Breslow thickness greater than 1.0 and less than or equal to 4 mm (pT2-pT3). Ann Surg Oncol. 2008;15:2223–34.

    Article  PubMed  Google Scholar 

  21. Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. New York: Springer; 1997. p. 282–6.

    Google Scholar 

  22. Thompson LW, Garbee CF, Hibbitts S, et al. Competition among peptides in melanoma vaccines for binding to MHC molecules. J Immunother. 2004;27:425–31.

    Article  PubMed  CAS  Google Scholar 

  23. Slingluff CL Jr, Petroni GR, Chianese-Bullock KA, et al. Immunologic and clinical outcomes of a randomized phase II trial of two multipeptide vaccines for melanoma in the adjuvant setting. Clin Cancer Res. 2007;13:6386–95.

    Article  PubMed  CAS  Google Scholar 

  24. Tsai V, Southwood S, Sidney J, et al. Identification of subdominant CTL epitopes of the gp100 melanoma-associated tumor antigen by primary in vitro immunization with peptide-pulsed dendritic cells. J Immunol. 1997;158:1796–802.

    PubMed  CAS  Google Scholar 

  25. Markowicz S, Engleman EG. Granulocyte-macrophage colony-stimulating factor promotes differentiation and survival of human peripheral blood dendritic cells in vitro. J Clin Invest. 1990;85:955–61.

    Article  PubMed  CAS  Google Scholar 

  26. Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J. GM-CSF and TNF-α cooperate in the generation of dendritic Langerhans cells. Nature. 1992;360:258–61.

    Article  PubMed  CAS  Google Scholar 

  27. Parmiani G, Castelli C, Pilla L, Santinami M, Colombo MP, Rivoltini L. Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Ann Oncol. 2007;18:226–32.

    Article  PubMed  CAS  Google Scholar 

  28. Eggermont AM. Immunostimulation versus immunosuppression after multiple vaccinations: the woes of therapeutic vaccine development. Clin Cancer Res. 2009;15:6745–7.

    Article  PubMed  CAS  Google Scholar 

  29. Faries MB, Hsueh EC, Ye X, Hoban M, Morton DL. Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine. Clin Cancer Res. 2009;15:7029–35.

    Article  PubMed  CAS  Google Scholar 

  30. Slingluff CL Jr, Petroni GR, Olson WC, et al. Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial. Clin Cancer Res. 2009;15:7036–44.

    Article  PubMed  CAS  Google Scholar 

  31. Gunturu KS, Meehan KR, Mackenzie TA, et al. Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery. J Clin Oncol. 2010;28:1196–202.

    Article  PubMed  CAS  Google Scholar 

  32. Santiago-Schwarz F, Belilos E, Diamond B, Carsons SE. TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages. J Leuk Biol. 1992;52:274–81.

    CAS  Google Scholar 

  33. Reid CDL, Stackpoole A, Meager A, Tikerpae J. Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow. J Immunol. 1992;149:2681–8.

    PubMed  CAS  Google Scholar 

  34. Young JW, Szabolcs P, Moore MAS. Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor α. J Exp Med. 1995;182:1111–9.

    Article  PubMed  CAS  Google Scholar 

  35. Siena S, Di Nicola M, Bregni M, et al. Massive ex vivo generation of functional dendritic cells from mobilized CD34+ blood progenitors for anticancer therapy. Exp Hematol. 1995;23:1463–71.

    PubMed  CAS  Google Scholar 

  36. Markowicz S, Walewski J, Kawecki A. Isolation and characteristic of dendritic cell progenitors from the bone marrow of the Hodgkin’s disease patients. In: Banchereau J, Schmitt D, editors. Dendritic cells in fundamental and clinical immunology, vol. 2. New York: Plenum Press; 1995. p. 553–5.

    Chapter  Google Scholar 

  37. Bernhard H, Disks ML, Heimfeld S, Hand S, Gralow JR, Cheever MA. Generation of immunostimulatory dendritic cells from human CD34+ hematopoietic progenitor cells of the bone marrow and peripheral blood. Cancer Res. 1995;55:1099–104.

    PubMed  CAS  Google Scholar 

  38. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994;179:1109–18.

    Article  PubMed  CAS  Google Scholar 

  39. Banerjee DK, Dhodapkar MV, Matayeva E, Steinman RM, Dhodapkar KM. Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood. 2006;108:2655–61.

    Article  PubMed  CAS  Google Scholar 

  40. Hayashi Y, Hoon DS, Park MS, Terasaki PI, Foshag LJ, Morton DL. Induction of CD4+ cytotoxic T cells by sensitization with allogeneic melanomas bearing shared or cross-reactive HLA-A. Cell Immunol. 1992;139:411–25.

    Article  PubMed  CAS  Google Scholar 

  41. Robbins PF, el-Gamil M, Li YF, et al. Cloning of a new gene encoding an antigen recognized by melanoma-specific HLA-A24-restricted tumor-infiltrating lymphocytes. J Immunol. 1995;154:5944–50.

    PubMed  CAS  Google Scholar 

  42. Darrow TL, Abdel-Wahab Z, Quinn-Allen MA, Seigler HF. Recognition and lysis of human melanoma by a CD3+, CD4+, CD8− T-cell clone restricted by HLA-A2. Cell Immunol. 1996;172:52–9.

    Article  PubMed  CAS  Google Scholar 

  43. Nishimura MI, Avichezer D, Custer MC, et al. MHC class I-restricted recognition of a melanoma antigen by a human CD4+ tumor infiltrating lymphocyte. Cancer Res. 1999;59:6230–8.

    PubMed  CAS  Google Scholar 

  44. Voelkl S, Moore TV, Rehli M, Nishimura MI, Mackensen A, Fischer K. Characterization of MHC class-I restricted TCRalphabeta+ CD4− CD8− double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination. Cancer Immunol Immunother. 2009;58:709–18.

    Article  PubMed  CAS  Google Scholar 

  45. Sosman JA, Unger JM, Liu PY, et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: impact of HLA class I antigen expression on outcome. J Clin Oncol. 2002;8:2067–75.

    Article  Google Scholar 

  46. Wolchok JD, Weber JS, Hamid O, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun. 2010;10:9–14.

    PubMed  Google Scholar 

  47. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Magdalena Rosinska for statistical assistance.

Conflict of interest

All authors declare that no conflict of interest exists.

Author information

Authors and Affiliations

  1. Department of Immunology, Maria Sklodowska-Curie Memorial Institute and Oncology Centre, ul. Roentgena 5, 02-781, Warszawa, Poland

    Sergiusz Markowicz, Marzena Biernacka, Anna Jakubowska-Mucka & Henryk Skurzak

  2. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warszawa, Poland

    Zbigniew I. Nowecki, Piotr Rutkowski & Tomasz Switaj

  3. Neuropeptide Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland

    Andrzej W. Lipkowski & Aleksandra Misicka

  4. Department of Microbiology, Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warszawa, Poland

    Hanna Polowniak-Pracka

  5. Department of Lymphoid Malignancies, Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warszawa, Poland

    Jan Walewski

Authors
  1. Sergiusz Markowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zbigniew I. Nowecki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Piotr Rutkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrzej W. Lipkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marzena Biernacka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna Jakubowska-Mucka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomasz Switaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aleksandra Misicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Henryk Skurzak
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hanna Polowniak-Pracka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jan Walewski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergiusz Markowicz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Markowicz, S., Nowecki, Z.I., Rutkowski, P. et al. Adjuvant vaccination with melanoma antigen-pulsed dendritic cells in stage III melanoma patients. Med Oncol 29, 2966–2977 (2012). https://doi.org/10.1007/s12032-012-0168-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-012-0168-1

Keywords

Search

Navigation