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[Cancer Research 62, 5792-5799, October 15, 2002]
© 2002 American Association for Cancer Research

Immunology

Establishment of an HLA-A*0201 Human Papillomavirus Type 16 Tumor Model to Determine the Efficacy of Vaccination Strategies in HLA-A*0201 Transgenic Mice1

Gretchen L. Eiben2, Markwin P. Velders2, Hans Schreiber, Maria Cristina Cassetti, Jeffrey K. Pullen, Larry R. Smith and W. Martin Kast3

Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois 60153 [G. L. E., M. P. V., W. M. K.]; Department of Pathology, University of Chicago, Chicago, Illinois 60637 [H. S.]; and Wyeth Research, Viral Vaccines Immunology, Pearl River, New York 10965 [M. C. C., J. K. P., L. R. S.]

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-2Db 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.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2002 by the American Association for Cancer Research.