title: A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients.
abstract: BACKGROUND
  Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
  
  
  METHODS
  In this phase IB clinical trial, 24 million viable DCs were administered by four biweekly combined intradermal (id) and intravenous (iv) administrations, and a fifth administration on week 16. The number of iv-administered DCs was escalated in four sequentially treated cohorts. Immune responses were assessed by analysis of antigen specificity of blood-derived T-cells and skin infiltrating lymphocytes (SKILs).
  
  
  RESULTS
  Fifteen patients with pretreated advanced melanoma tolerated administration of TriMixDC-MEL well. Two patients achieved a complete response and two patients a partial response. All objective responders are progression-free after a follow-up of, respectively, 24+, 28+, 33+, and 34+ months. Post-therapy antigen-specific SKILs were documented in 6 of 12 patients, and antigen-specific CD8(+) T-cells were detected in the blood of 4 of 5 patients.
  
  
  CONCLUSIONS
  Cellular immunotherapy with TriMixDC-MEL is safe and immunogenic. Antitumor activity with durable disease control is observed across the investigated iv-dose levels.
  
  
  BACKGROUND
  NCT01066390.
authors.affiliation: Departments of Medical Oncology; The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Wilgenhof
authors.affiliation: The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: A M T
authors.initials: AMT
authors.lastname: Van Nuffel
authors.affiliation: The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Benteyn
authors.affiliation: The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Corthals
authors.affiliation: The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Aerts
authors.affiliation: The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Heirman
authors.affiliation: Clinical Hematology UZ Brussel.
authors.forename: I
authors.initials: I
authors.lastname: Van Riet
authors.affiliation: The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Bonehill
authors.affiliation: Departments of Medical Oncology; The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Thielemans
authors.affiliation: Departments of Medical Oncology; The Laboratory of Molecular and Cellular Therapy and Dendritic Cell Bank of the 'Vrije Universiteit Brussel', Brussels, Belgium. Electronic address: bart.neyns@uzbrussel.be.
authors.forename: B
authors.initials: B
authors.lastname: Neyns
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D053282:CD27 Ligand / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D018572:Disease-Free Survival; D018274:Electroporation; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D059666:Lysosomal-Associated Membrane Protein 3 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000628:therapy*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D053282:CD27 Ligand; D059666:Lysosomal-Associated Membrane Protein 3; C072013:MAGEA3 protein, human; C405429:MAGEC2 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand; D014442:Monophenol Monooxygenase
keywords: TriMixDC-MEL; dendritic cells; immunotherapy; melanoma