title: Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.
abstract: Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail.
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.|Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Kalijn F
authors: KF
authors: Bol
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.|Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Erik H J G
authors: EH
authors: Aarntzen
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Jeanette M
authors: JM
authors: Pots
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Michel A M
authors: MA
authors: Olde Nordkamp
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Mandy W M M
authors: MW
authors: van de Rakt
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Nicole M
authors: NM
authors: Scharenborg
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Annemiek J
authors: AJ
authors: de Boer
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Tom G M
authors: TG
authors: van Oorschot
authors: Department of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Sandra A J
authors: SA
authors: Croockewit
authors: Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Willeke A M
authors: WA
authors: Blokx
authors: Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Wim J G
authors: WJ
authors: Oyen
authors: Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Otto C
authors: OC
authors: Boerman
authors: Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Roel D M
authors: RD
authors: Mus
authors: Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Michelle M
authors: MM
authors: van Rossum
authors: Department of Pulmonary Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Chantal A A
authors: CA
authors: van der Graaf
authors: Department of Medical Oncology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Cornelis J A
authors: CJ
authors: Punt
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Gosse J
authors: GJ
authors: Adema
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Carl G
authors: CG
authors: Figdor
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.|Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: I Jolanda M
authors: IJ
authors: de Vries
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Gerty.Schreibelt@radboudumc.nl.
authors: Gerty
authors: G
authors: Schreibelt
mesh_terms: D000328:Adult; D000368:Aged; D001500:BCG Vaccine / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology*; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D019496:Cancer Vaccines; D058951:gp100 Melanoma Antigen; D006433:Hemocyanins; D014442:Monophenol Monooxygenase; C032808:keyhole-limpet hemocyanin; D015232:Dinoprostone
keywords: Dendritic cells; Immunotherapy; Maturation; Melanoma; Prophylactic vaccines; Toll-like receptor ligands