Advertisement

Towards a Standardized Protocol for the Generation of Monocyte-Derived Dendritic Cell Vaccines

  • Michael Erdmann
  • Beatrice Schuler-Thurner
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 595)

Abstract

For more than one decade patients have been treated with dendritic cell (DC) immunotherapy against malignancies and infectious diseases. Proof of principle studies demonstrated immunogenicity and clinical responses were observed in a fraction of patients. Overlooking more than 200 publications one realizes, however, that it is almost impossible to compare many of these trials even in a given clinical setting or disease. This is primarily due to the fact that dendritic cell generation procedures are highly variable. There is a requirement for a standardized DC generation protocol which provides ‘reference dendritic cells’ to which other dendritic cells (e.g. differently matured ones) can be compared to in order to further optimize this promising vaccination approach.

In this chapter, we describe in detail our standard DC generation protocols established during the last decade with over 200 melanoma patients treated and over 2,000 vaccinations applied in clinical studies at our hospital. We do not claim that these dendritic cells are the best ones, but the generation procedure is highly reliable and reproducible and provides a standardized reference DC vaccine.

Key words

Dendritic cell monocyte-derived dendritic cell monocyte counterflow elutriation GMP 

Notes

Acknowledgments

This work was supported by grants to Gerold Schuler, Department of Dermatology, University Hospital of Erlangen from the DFG – German Research Foundation (Collaborative Research Centre SFB643, Project C1), the European Union (DC-THERA Dendritic cells & Novel Immunotherapies, Network of Excellence, Project Number 512074) and by the Cancer Immunotherapy (CIMT) EU Integrated Project WP02.02.

References

  1. 1.
    Hauschild, A., Gogas, H., Tarhini, A., Middleton, M. R., Testori, A., Dreno, B., and Kirkwood, J. M. (2008) Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer 112, 982–94.CrossRefPubMedGoogle Scholar
  2. 2.
    Rosenberg, S. A., Lotze, M. T., Yang, J. C., Topalian, S. L., Chang, A. E., Schwartzentruber, D. J., Aebersold, P., Leitman, S., Linehan, W. M., Seipp, C. A., and et al. (1993) Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 85, 622–32.CrossRefPubMedGoogle Scholar
  3. 3.
    Phan, G. Q., Yang, J. C., Sherry, R. M., Hwu, P., Topalian, S. L., Schwartzentruber, D. J., Restifo, N. P., Haworth, L. R., Seipp, C. A., Freezer, L. J., Morton, K. E., Mavroukakis, S. A., Duray, P. H., Steinberg, S. M., Allison, J. P., Davis, T. A., and Rosenberg, S. A. (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100, 8372–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Scheibenbogen, C., Letsch, A., Schmittel, A., Asemissen, A. M., Thiel, E., and Keilholz, U. (2003) Rational peptide-based tumour vaccine development and T cell monitoring Semin. Cancer Biol 13, 423–9.CrossRefGoogle Scholar
  5. 5.
    Weide, B., Garbe, C., Rammensee, H. G., and Pascolo, S. (2008) Plasmid DNA- and messenger RNA-based anti-cancer vaccination. Immunol Lett 115, 33–42.CrossRefPubMedGoogle Scholar
  6. 6.
    Dudley, M. E., Wunderlich, J. R., Robbins, P. F., Yang, J. C., Hwu, P., Schwartzentruber, D. J., Topalian, S. L., Sherry, R., Restifo, N. P., Hubicki, A. M., Robinson, M. R., Raffeld, M., Duray, P., Seipp, C. A., Rogers-Freezer, L., Morton, K. E., Mavroukakis, S. A., White, D. E., and Rosenberg, S. A. (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Steinman, R. M. (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9, 271–96.CrossRefPubMedGoogle Scholar
  8. 8.
    Erdmann, M., and Schuler-Thurner, B. (2008) Dendritic cell vaccines in metastasized malignant melanoma. G Ital Dermatol Venereol 143, 235–50.PubMedGoogle Scholar
  9. 9.
    Schuler-Thurner, B., Dieckmann, D., Keikavoussi, P., Bender, A., Maczek, C., Jonuleit, H., Roder, C., Haendle, I., Leisgang, W., Dunbar, R., Cerundolo, V., von Den Driesch, P., Knop, J., Brocker, E. B., Enk, A., Kampgen, E., and Schuler, G. (2000) Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1+ melanoma patients by mature monocyte-derived dendritic cells. J Immunol 165, 3492–6.PubMedGoogle Scholar
  10. 10.
    Schuler-Thurner, B., Schultz, E. S., Berger, T. G., Weinlich, G., Ebner, S., Woerl, P., Bender, A., Feuerstein, B., Fritsch, P. O., Romani, N., and Schuler, G. (2002) Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 195, 1279–88.CrossRefPubMedGoogle Scholar
  11. 11.
    Thurner, B., Haendle, I., Roder, C., Dieckmann, D., Keikavoussi, P., Jonuleit, H., Bender, A., Maczek, C., Schreiner, D., von den Driesch, P., Brocker, E. B., Steinman, R. M., Enk, A., Kampgen, E., and Schuler, G. (1999) Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190, 1669–78.CrossRefPubMedGoogle Scholar
  12. 12.
    Schadendorf, D., Ugurel, S., Schuler-Thurner, B., Nestle, F. O., Enk, A., Brocker, E. B., Grabbe, S., Rittgen, W., Edler, L., Sucker, A., Zimpfer-Rechner, C., Berger, T., Kamarashev, J., Burg, G., Jonuleit, H., Tuttenberg, A., Becker, J. C., Keikavoussi, P., Kampgen, E., and Schuler, G. (2006) 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 17, 563–70.CrossRefPubMedGoogle Scholar
  13. 13.
    Banchereau, J., Palucka, A. K., Dhodapkar, M., Burkeholder, S., Taquet, N., Rolland, A., Taquet, S., Coquery, S., Wittkowski, K. M., Bhardwaj, N., Pineiro, L., Steinman, R., and Fay, J. (2001) Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 61, 6451–8.PubMedGoogle Scholar
  14. 14.
    Fong, L., Hou, Y., Rivas, A., Benike, C., Yuen, A., Fisher, G. A., Davis, M. M., and Engleman, E. G. (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA 98, 8809–14.CrossRefPubMedGoogle Scholar
  15. 15.
    Berger, T. G., Feuerstein, B., Strasser, E., Hirsch, U., Schreiner, D., Schuler, G., and Schuler-Thurner, B. (2002) Large-scale generation of mature monocyte-derived dendritic cells for clinical application in cell factories. J Immunol Methods 268, 131–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Babatz, J., Rollig, C., Oelschlagel, U., Zhao, S., Ehninger, G., Schmitz, M., and Bornhauser, M. (2003) Large-scale immunomagnetic selection of CD14+ monocytes to generate dendritic cells for cancer immunotherapy: a phase I study. J Hematother Stem Cell Res 12, 515–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Di Nicola, M., Carlo-Stella, C., Mortarini, R., Baldassari, P., Guidetti, A., Gallino, G. F., Del Vecchio, M., Ravagnani, F., Magni, M., Chaplin, P., Cascinelli, N., Parmiani, G., Gianni, A. M., and Anichini, A. (2004) Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34(+)-derived dendritic cell vaccination: a phase I trial in metastatic melanoma Clin. Cancer Res 10, 5381–90.CrossRefGoogle Scholar
  18. 18.
    Holtl, L., Ramoner, R., Zelle-Rieser, C., Gander, H., Putz, T., Papesh, C., Nussbaumer, W., Falkensammer, C., Bartsch, G., and Thurnher, M. (2005) Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol Immunother 54, 663–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Berger, T. G., Strasser, E., Smith, R., Carste, C., Schuler-Thurner, B., Kaempgen, E., and Schuler, G. (2005) Efficient elutriation of monocytes within a closed system (Elutra) for clinical-scale generation of dendritic cells. J Immunol Methods 298, 61–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Erdmann, M., Dorrie, J., Schaft, N., Strasser, E., Hendelmeier, M., Kampgen, E., Schuler, G., and Schuler-Thurner, B. (2007) Effective clinical-scale production of dendritic cell vaccines by monocyte elutriation directly in medium, subsequent culture in bags and final antigen loading using peptides or RNA transfection. J Immunother 30, 663–74.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Michael Erdmann
    • 1
  • Beatrice Schuler-Thurner
    • 1
  1. 1.Department of DermatologyUniversity Hospital of ErlangenErlangenGermany

Personalised recommendations