Establishment of an HLA-A0201 human papillomavirus type 16 tumor model to determine the efficacy of vaccination strategies in HLA-A0201 transgenic mice

• Published in: Cancer research (Chicago, Ill.) Vol. 62; no. 20; pp. 5792 - 5799
• Main Authors: EIBEN, Gretchen L, VELDERS, Markwin P, SCHREIBER, Hans, CASSETTI, Maria Cristina, PULLEN, Jeffrey K, SMITH, Larry R, KAST, W. Martin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2002
• Subjects: Animal tumors. Experimental tumors; Animals; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - genetics; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Disease Models, Animal; Encephalitis Virus, Venezuelan Equine; Epitopes - immunology; Experimental tumors, general aspects; Female; HLA-A Antigens - immunology; HLA-A2 Antigen; Immunotherapy; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Oncogene Proteins, Viral - immunology; Papillomavirus E7 Proteins; Pharmacology. Drug treatments; Repressor Proteins; Tumors; Vaccines, DNA - genetics; Vaccines, DNA - immunology; Vaccines, DNA - therapeutic use; Antineoplastic agent; Animal model; HLA-System; Antigenic determinant; Major histocompatibility system; Vaccination; Transgenic animal; Papovaviridae; Papillomavirus; Human papillomavirus 16; Human papillomavirus; HLA-A-Locus; Immunotherapy; Class I histocompatibility antigen; Immune response; Rodentia; Malignant tumor; Gene expression; Genetic vaccine; Virus; Vertebrata; Mammalia; Treatment; Histocompatibility restriction; Mouse; Oncogenic virus; Animal; Oncoprotein; Onc gene
• ISSN: 0008-5472; 1538-7445

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.