title: Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient.
abstract: Dendritic cells (DCs) electroporated with mRNA encoding CD70, CD40L and a constitutively active toll-like receptor 4 (TriMix-DC) have an increased T-cell stimulatory capacity. In a prospective phase IB clinical trial, we treated melanoma patients with intradermal and intravenous injections of autologous TriMix-DC co-electroporated with mRNA encoding full-length MAGE-A3, MAGE-C2, tyrosinase and gp100. We report here the immunological and clinical results obtained in one patient with a particularly favorable outcome. This patient had stage IV-M1c melanoma with documented progression during dacarbazine chemotherapy and received 5 TriMix-DC injections. Following DC therapy, a broad CD8(+) T-cell response against multiple epitopes derived from all four treatment antigens was found in the blood and among T cells derived from DTH biopsy. In addition, CD4(+) T cells recognizing different MAGE-A3-derived epitopes were detected in DTH-derived cells. A spontaneous anti-MAGE-C2 CD8(+) T-cell response was present prior to TriMix-DC therapy and increased during treatment. The tumor response was assessed with 18-fluorodeoxyglucose-positron emission/computed tomography. We documented a partial tumor response according to RECIST criteria with a marked reduction in (18)F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Belgium.
authors.forename: An M T
authors.initials: AM
authors.lastname: Van Nuffel
authors.forename: Daphné
authors.initials: D
authors.lastname: Benteyn
authors.forename: Sofie
authors.initials: S
authors.lastname: Wilgenhof
authors.forename: Jurgen
authors.initials: J
authors.lastname: Corthals
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Aude
authors.initials: A
authors.lastname: Bonehill
mesh_terms: D000595:Amino Acid Sequence; D053282:CD27 Ligand / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D018274:Electroporation / Q000379:methods; D006371:Helium / Q000008:administration & dosage*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D009584:Nitrogen / Q000008:administration & dosage*; D010100:Oxygen / Q000008:administration & dosage*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D053282:CD27 Ligand; C505771:CD70 protein, human; D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand; D006371:Helium; C045257:trimix; D009584:Nitrogen; D010100:Oxygen