title: Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients.
abstract: Autologous dendritic cell (DC) therapy is an experimental cellular immunotherapy that is safe and immunogenic in patients with advanced melanoma. In an attempt to further improve the therapeutic responses, we treated 15 patients with melanoma, with autologous monocyte-derived immature DC electroporated with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively active TLR4 (caTLR4) together with mRNA encoding a tumor-associated antigen (TAA; respectively gp100 or tyrosinase). In addition, DC were pulsed with keyhole limpet hemocyanin (KLH) that served as a control antigen. Production of this DC vaccine with high cellular viability, high expression of co-stimulatory molecules and MHC class I and II and production of IL-12p70, was feasible in all patients. A vaccination cycle consisting of three vaccinations with up to 15×106DC per vaccination at a biweekly interval, was repeated after 6 and 12 months in the absence of disease progression. mRNA-optimized DC were injected intranodally, because of low CCR7 expression on the DC, and induced de novo immune responses against control antigen. T cell responses against tyrosinase were detected in the skin-test infiltrating lymphocytes (SKIL) of two patients. One mixed tumor response and two durable tumor stabilizations were observed among 8 patients with evaluable disease at baseline. In conclusion, autologous mRNA-optimized DC can be safely administered intranodally to patients with metastatic melanoma but showed limited immunological responses against tyrosinase and gp100.
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands ; Medical Oncology; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Kalijn F
authors.initials: KF
authors.lastname: Bol
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands ; Radiology and Nuclear Medicine; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Erik Hjg
authors.initials: EH
authors.lastname: Aarntzen
authors.affiliation: Pharmacy; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Marieke Eb
authors.initials: ME
authors.lastname: Welzen
authors.affiliation: Dermatology; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: van Rossum
authors.affiliation: Pathology; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Willeke Am
authors.initials: WA
authors.lastname: Blokx
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Mandy Wmm
authors.initials: MW
authors.lastname: van de Rakt
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Scharenborg
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Annemiek J
authors.initials: AJ
authors.lastname: de Boer
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Pots
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Michel Am
authors.initials: MA
authors.lastname: Olde Nordkamp
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Tom Gm
authors.initials: TG
authors.lastname: van Oorschot
authors.affiliation: Radiology and Nuclear Medicine; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Roel Dm
authors.initials: RD
authors.lastname: Mus
authors.affiliation: Hematology; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Sandra Aj
authors.initials: SA
authors.lastname: Croockewit
authors.affiliation: Laboratory Medicine; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Joannes Fm
authors.initials: JF
authors.lastname: Jacobs
authors.affiliation: Department of Dermatology; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Gerold
authors.initials: G
authors.lastname: Schuler
authors.affiliation: Department of Medical Oncology; Vrije Universiteit Brussel ; Brussels, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.affiliation: Nuffield Department of Surgical Sciences; John Radcliffe Hospital; University of Oxford ; Oxford, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Austyn
authors.affiliation: Department of Medical Oncology; Academic Medical Center ; Amsterdam, The Netherlands.
authors.forename: Cornelis Ja
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: Gerty
authors.initials: G
authors.lastname: Schreibelt
authors.affiliation: Department of Tumor Immunology (Radboud Institute for Molecular Life Sciences); Radboud university medical centre ; Nijmegen, The Netherlands ; Medical Oncology; Radboud university medical centre ; Nijmegen, The Netherlands.
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
keywords: DC vaccines; dendritic cell; immunotherapy; mRNA electroporation; melanoma