title: Establishment of an HLA-A*0201 human papillomavirus type 16 tumor model to determine the efficacy of vaccination strategies in HLA-A*0201 transgenic mice.
abstract: With the increasing generation of new cancer vaccine strategies, there is also an increasing demand for preclinical models that can carefully predict the efficacy of these vaccines in humans. However, the only tumor models available to study vaccines against human papillomavirus (HPV) 16 have been developed in C57BL/6 mice. To test the HLA-restricted capabilities of vaccination strategies, it is important to establish a tumor model in HLA-A*0201 transgenic mice. By transfecting heart lung fibroblasts from HLA-A*0201 mice with HPV16 E6 and E7 oncogenes and H-Ras V12, we have generated a transgenic cell line that is tumorigenic in HLA-A*0201 mice. The dominant H-2D(b) HPV16 E7 epitope was removed from the E7 construct to ensure that all antitumor responses were mediated through the HLA-A*0201-restricted epitopes. We used this tumor model to test the efficacy of two genetic vaccines: a plasmid DNA multi-epitope vaccine encoding human epitopes of HPV16, and a Venezuelan equine encephalitis (VEE) virus-based vector to deliver HPV16 E6 and E7 RNA. We show that both our multi-epitope DNA- and VEE-based vaccines protect 100% of HLA-A*0201 transgenic mice from tumor challenge and elicit a specific T-cell response against multiple HLA-A*0201-restricted HPV16 epitopes. Furthermore, both vaccines significantly decreased tumor burden when tested therapeutically. In conclusion, this is the first tumor model that allows for the assessment of the potential of a vaccine to induce HPV-directed, HLA-A*0201-restricted, antitumor responses in mice. These results pave the way for the clinical evaluation of these vaccines.
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois 60153, USA.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Eiben
authors.forename: Markwin P
authors.initials: MP
authors.lastname: Velders
authors.forename: Hans
authors.initials: H
authors.lastname: Schreiber
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Cassetti
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Pullen
authors.forename: Larry R
authors.initials: LR
authors.lastname: Smith
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004666:Encephalitis Virus, Venezuelan Equine; D000939:Epitopes / Q000276:immunology; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16