title: Therapeutic vaccination with an autologous mRNA electroporated dendritic cell vaccine in patients with advanced melanoma.
abstract: The immunostimulatory capacity of dendritic cells is improved by co-electroporation with mRNA encoding CD40 ligand, constitutively active toll-like receptor 4, and CD70 (TriMix-DC). This pilot clinical trial evaluated the feasibility, safety, and immunogenicity of a therapeutic vaccination containing autologous TriMix-DC co-electroporated with mRNA encoding a human leukocyte antigen class II-targeting signal linked to 1 of 4 melanoma-associated antigens (MAGE-A3, MAGE-C2, tyrosinase, and gp100) in patients with advanced melanoma. Thirty-five American Joint Committee on Cancer stage III/IV melanoma patients received autologous TriMix-DC (4 administrations 2 weeks apart). Immune monitoring was performed by evaluating skin biopsies of delayed type IV hypersensitivity (DTH) reactions for presence of vaccinal antigen-specific DTH-infiltrating lymphocytes (DIL). Thereafter, patients could receive interferon-alpha-2b (IFN-α-2b) 5 MU subcutaneously 3 times weekly and additional TriMix-DC every 8 weeks. TriMix-DC-related adverse events comprised grade 2 local injection site reactions (all patients), and grade 2 fever and lethargy (2 patients). Vaccinal antigen-specific DIL were found in 0/6 patients tested at vaccine initiation and in 12/21 (57.1%) assessed after the fourth vaccine. A positive postvaccination DTH test correlated with IL-12p70 secretion capacity of TriMix-DC. No objective responses to TriMix-DC alone were seen according to RECIST. Twenty-nine patients received IFN-α-2b after the fourth vaccine without unexpected adverse events. During TriMix-DC/IFN-α-2b combination therapy, 1 partial response and 5 stable disease (disease control of >6 months with regression of metastases) were observed in 17 patients with evaluable disease at baseline. In conclusion, this study demonstrated that therapeutic vaccination with autologous TriMix-DC is feasible, safe, and immunogenic and can be combined with sequential IFN-α-2b.
authors.affiliation: Department of Medical Oncology, Brussels, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Wilgenhof
authors.forename: An M T
authors.initials: AM
authors.lastname: Van Nuffel
authors.forename: Jurgen
authors.initials: J
authors.lastname: Corthals
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.forename: Sandra
authors.initials: S
authors.lastname: Tuyaerts
authors.forename: Daphné
authors.initials: D
authors.lastname: Benteyn
authors.forename: Arlette
authors.initials: A
authors.lastname: De Coninck
authors.forename: Ivan
authors.initials: I
authors.lastname: Van Riet
authors.forename: Guy
authors.initials: G
authors.lastname: Verfaillie
authors.forename: Judith
authors.initials: J
authors.lastname: Vandeloo
authors.forename: Aude
authors.initials: A
authors.lastname: Bonehill
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D053282:CD27 Ligand / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000379:methods*; D018274:Electroporation; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D053282:CD27 Ligand; D019013:CD40 Antigens; D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4