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Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma

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Abstract

Background: Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer. Patients and methods: Autologous DC of HLA-A*0201+ patients with hormone-refractory prostate cancer were loaded with antigenic peptides derived from prostate stem cell antigen (PSCA14–22), prostatic acid phosphatase (PAP299–307), prostate-specific membrane antigen (PSMA4–12), and prostate-specific antigen (PSA154–163). DC were intradermally applied six times at biweekly intervals followed—in the case of an enhanced immune response—by monthly booster injections. Immune monitoring during the time of ongoing vaccinations (12–59 weeks) included ex vivo ELISPOT measurements, MHC tetramer analysis and in vitro cytotoxicity assays. Results: Of the initial six patients, three qualified for long-term multi-epitope DC vaccination. This regime was tolerated well by all three patients. The vaccination elicited significant cytotoxic T cell responses against all prostate-specific antigens tested. In addition, memory T cell responses against the control peptides derived from influenza matrix protein and tetanus toxoid were efficiently boosted. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time. Conclusions: DC-based multi-epitope immunotherapy with repeated boosting in men with hormone-refractory prostate carcinoma is feasible and generates efficient cellular antitumor responses.

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Abbreviations

CTL:

Cytotoxic T lymphocytes

DC:

Dendritic cells

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

IL:

Interleukin

mAb:

Monoclonal antibody

PAP:

Prostatic acid phosphatase

PBMC:

Peripheral blood mononuclear cells

PSA:

Prostate-specific antigen

PSCA:

Prostate stem cell antigen

PSMA:

Prostate-specific membrane antigen

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Acknowledgements

We thank R. Steingruber for clinical assistance and Dr. Gennady Bocharov for help with biostatistical calculations. We thank Dr. J. Hering and the personnel from the regional blood donation center SRC. Dr. Brendan Classon in Avidex Ltd., Abingdon, UK is acknowledged for providing PSCA tetramers.

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Correspondence to Silke Gillessen.

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Grant sponsors: Cancer League St. Gallen-Appenzell; Swiss Cancer League; Foundation Propter Homines Vaduz Liechtenstein; Cancer Research Institute USA; Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK)

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Waeckerle-Men, Y., Uetz-von Allmen, E., Fopp, M. et al. Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma. Cancer Immunol Immunother 55, 1524–1533 (2006). https://doi.org/10.1007/s00262-006-0157-3

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