title: Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients.
abstract: BACKGROUND
  Current approaches for treating metastatic malignant melanoma (MM) are not effective enough and are associated with serious adverse events. Due to its immunogenicity, melanoma is an attractive target for immunostimulating therapy. In this phase I/IIa study, local AdCD40L immunostimulatory gene therapy was evaluated in patients with MM.
  
  
  METHODS
  AdCD40L is an adenovirus carrying the gene for CD40 ligand. Patients that failed standard treatments were enrolled. Six patients received four weekly intratumoral AdCD40L injections. Next, nine patients received low-dose cyclophosphamide conditioning before the first and fourth AdCD40L injection. The blood samples were collected at multiple time points for chemistry, haematology and immunology evaluations. Radiology was performed at enrolment and repeated twice after the treatment.
  
  
  RESULTS
  AdCD40L was safe with mild transient reactions. No objective responses were recorded by MRI, however, local and distant responses were seen on FDG-PET. The overall survival at 6 months was significantly better when cyclophosphamide was added to AdCD40L. The patients with the best survival developed the highest levels of activated T cells and experienced a pronounced decrease of intratumoral IL8.
  
  
  CONCLUSIONS
  AdCD40L therapy for MM was well tolerated. Local and distant responses along with better survival in the low-dose cyclophosphamide group are encouraging.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.
authors.forename: Angelica
authors.initials: A
authors.lastname: Loskog
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.|Department of Oncology, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Aglaia
authors.initials: A
authors.lastname: Maleka
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Mangsbo
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Svensson
authors.affiliation: Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Lundberg
authors.affiliation: Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Nilsson
authors.affiliation: Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Krause
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.|Department of Pathology and Cytology, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Margrét
authors.initials: M
authors.lastname: Agnarsdóttir
authors.affiliation: Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden.|Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundin
authors.affiliation: Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden.|Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Ahlström
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Tötterman
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.|Department of Oncology, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Gustav
authors.initials: G
authors.lastname: Ullenhag
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D023201:CD40 Ligand / Q000008:administration & dosage*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000628:therapy*; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D023201:CD40 Ligand; D003520:Cyclophosphamide