title: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.
abstract: OBJECTIVE
  Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer.
  
  
  METHODS
  Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 x 10(6), 4 x 10(6), or 1 x 10(7) tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals.
  
  
  RESULTS
  Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106 cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.
  
  
  CONCLUSIONS
  Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Soiffer
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Frank
authors.initials: F
authors.lastname: Haluska
authors.forename: Ken
authors.initials: K
authors.lastname: Jung
authors.forename: Silke
authors.initials: S
authors.lastname: Gillessen
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Tanabe
authors.forename: Rosemary
authors.initials: R
authors.lastname: Duda
authors.forename: Steven
authors.initials: S
authors.lastname: Mentzer
authors.forename: Michael
authors.initials: M
authors.lastname: Jaklitsch
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.forename: Shirley
authors.initials: S
authors.lastname: Clift
authors.forename: Steve
authors.initials: S
authors.lastname: Hardy
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Richard
authors.initials: R
authors.lastname: Mulligan
authors.forename: Iain
authors.initials: I
authors.lastname: Webb
authors.forename: Martin
authors.initials: M
authors.lastname: Mihm
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: D000256:Adenoviridae; D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D003131:Combined Modality Therapy; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005818:Genetic Engineering; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006968:Hypersensitivity, Delayed; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor