title: Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma.
abstract: OBJECTIVE
  Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu(+) appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease.
  
  
  METHODS
  Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 × 10(8), 5 × 10(8), 1 × 10(9), or 3.3 × 10(9) CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations.
  
  
  RESULTS
  Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFNγ responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu(+) appendicular osteosarcoma treated with amputation and chemotherapy alone.
  
  
  CONCLUSIONS
  These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu(+) cancers. Clin Cancer Res; 22(17); 4380-90. ©2016 AACR.
authors.affiliation: Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania. Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania. nmason@vet.upenn.edu.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Mason
authors.affiliation: Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
authors.forename: Josephine S
authors.initials: JS
authors.lastname: Gnanandarajah
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Engiles
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
authors.forename: Falon
authors.initials: F
authors.lastname: Gray
authors.affiliation: Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
authors.forename: Danielle
authors.initials: D
authors.lastname: Laughlin
authors.affiliation: Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Anita
authors.initials: A
authors.lastname: Gaurnier-Hausser
authors.affiliation: Advaxis Inc., Princeton, New Jersey.
authors.forename: Anu
authors.initials: A
authors.lastname: Wallecha
authors.affiliation: ClinData Services Inc., Fort Collins, Colorado.
authors.forename: Margie
authors.initials: M
authors.lastname: Huebner
authors.affiliation: Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Paterson
mesh_terms: D000818:Animals; D015415:Biomarkers; D001859:Bone Neoplasms / Q000662:veterinary*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D018450:Disease Progression; D004283:Dog Diseases / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D004285:Dogs; D007111:Immunity, Cellular; D007115:Immunization Schedule; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma; D008087:Listeria / Q000276:immunology*; D012516:Osteosarcoma / Q000662:veterinary*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination; D014614:Vaccines, Synthetic
chemical_list: D015415:Biomarkers; D019496:Cancer Vaccines; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; D014614:Vaccines, Synthetic