title: Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the Animal Medical Center.
abstract: BACKGROUND
  Canine malignant melanoma (CMM) is an aggressive neoplasm treated with surgery and/or fractionated RT; however, metastatic disease is common and chemoresistant. Preclinical and clinical studies by our laboratory and others have shown that xenogeneic DNA vaccination with tyrosinase family members can produce immune responses resulting in tumor rejection or protection and prolongation of survival. These studies provided the impetus for development of a xenogeneic DNA vaccine program in CMM.
  
  
  METHODS
  Cohorts of three dogs each received increasing doses of xenogeneic plasmid DNA encoding either human tyrosinase (huTyr; 100/500/1500 mcg), murine GP75 (muGP75; 100/500/1500 mcg), murine tyrosinase (muTyr; 5 dogs each at 100/500 mcg), muTyr+/-HuGM-CSF (9 dogs at 50 mcg muTyr, 3 dogs each at 100/400/800 mcg HuGM-CSF, or 3 dogs each at 50 mcg muTyr with 100/400/800 mcg HuGM-CSF), or 50 mcg MuTyr intramuscularly biweekly for a total of four vaccinations.
  
  
  RESULTS
  The Kaplan-Meier median survival time (KM MST) for all stage II-IV dogs treated with huTyr, muGP75 and muTyr are 389, 153 and 224 days, respectively. Preliminarily, the KM MST for stage II-IV dogs treated with 50 mcg MuTyr, 100/400/800 mcg HuGM-CSF or combination MuTyr/HuGM-CSF are 242, 148 and >402 (median not reached) days, respectively. Thirty-three stage II-III dogs with loco-regionally controlled CMM across the xenogeneic vaccine studies have a KM MST of 569 days. Minimal to mild pain was noted on vaccination and one dog experienced vitiligo. We have recently investigated antibody responses in dogs vaccinated with HuTyr and found 2- to 5-fold increases in circulating antibodies to human tyrosinase.
  
  
  CONCLUSIONS
  The results of these trials demonstrate that xenogeneic DNA vaccination in CMM: (1) is safe, (2) leads to the development of anti-tyrosinase antibodies, (3) is potentially therapeutic, and (4) is an attractive candidate for further evaluation in an adjuvant, minimal residual disease Phase II setting for CMM.
authors.affiliation: Donaldson-Atwood Cancer Clinic & Flaherty Comparative Oncology Laboratory, The Animal Medical Center, 510 East 62nd Street, New York, NY 10021, USA. philip.bergman@amcny.org
authors.forename: P J
authors.initials: PJ
authors.lastname: Bergman
authors.forename: M A
authors.initials: MA
authors.lastname: Camps-Palau
authors.forename: J A
authors.initials: JA
authors.lastname: McKnight
authors.forename: N F
authors.initials: NF
authors.lastname: Leibman
authors.forename: D M
authors.initials: DM
authors.lastname: Craft
authors.forename: C
authors.initials: C
authors.lastname: Leung
authors.forename: J
authors.initials: J
authors.lastname: Liao
authors.forename: I
authors.initials: I
authors.lastname: Riviere
authors.forename: M
authors.initials: M
authors.lastname: Sadelain
authors.forename: A E
authors.initials: AE
authors.lastname: Hohenhaus
authors.forename: P
authors.initials: P
authors.lastname: Gregor
authors.forename: A N
authors.initials: AN
authors.lastname: Houghton
authors.forename: M A
authors.initials: MA
authors.lastname: Perales
authors.forename: J D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000818:Animals; D000917:Antibody Formation; D004283:Dog Diseases / Q000628:therapy*; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D008545:Melanoma / Q000628:therapy / Q000662:veterinary*; D014442:Monophenol Monooxygenase / Q000276:immunology; D019444:Vaccines, DNA / Q000627:therapeutic use*
chemical_list: D019444:Vaccines, DNA; D014442:Monophenol Monooxygenase