title: An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity.
abstract: OBJECTIVE
  Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in immunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use.
  
  
  METHODS
  We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo.
  
  
  RESULTS
  Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo.
  
  
  CONCLUSIONS
  Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials.
authors.affiliation: Department of Surgery, Medicine, Division of Medical Oncology, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Junping
authors.initials: J
authors.lastname: Wei
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Oliver
authors.initials: O
authors.lastname: Glass
authors.forename: Gangjun
authors.initials: G
authors.lastname: Lei
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Sharon
authors.initials: S
authors.lastname: Peplinski
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Wenle
authors.initials: W
authors.lastname: Xia
authors.forename: Neil
authors.initials: N
authors.lastname: Spector
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Marks
authors.forename: William
authors.initials: W
authors.lastname: Barry
authors.forename: Amy
authors.initials: A
authors.lastname: Hobeika
authors.forename: Gayathri
authors.initials: G
authors.lastname: Devi
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D018734:Genes, erbB-2 / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014611:Vaccination / Q000379:methods*
chemical_list: D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases