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Eradication of Established Tumors by Vaccination with Venezuelan Equine Encephalitis Virus Replicon Particles Delivering Human Papillomavirus 16 E7 RNA¹

Cardinal Bernardin Cancer Center, Loyola University-Chicago, Maywood, Illinois 60153 [M. P. V., G. L. E., A. G. E., W. M. K.], and Wyeth-Lederle Vaccines, Pearl River, New York 10965 [S. M., M. C. C., T. H., G. R. K., L. R. S.]

The etiological role of human papillomaviruses (HPV) in cervical and other cancers suggests that therapeutic vaccines directed against requisite viral antigens may eradicate tumors or their precursors. A Venezuelan equine encephalitis (VEE) alphavirus vector delivering the HPV16 E7 RNA was evaluated for antitumor efficacy using a murine E7⁺ tumor model. Vaccination with VEE replicon particles expressing E7 (E7-VRP) induced class I-restricted CD8⁺ T-cell responses as determined by IFN- enzyme-linked immunospot (ELISPOT), tetramer, and cytotoxicity assays. E7-VRP vaccination prevented tumor development in all of the mice and effectively eliminated 7-day established tumors in 67% of tumor-bearing mice. The induction of protective T-cell responses was dependent on CD8⁺, but not CD4⁺ T cells. Long-lasting T-cell memory responses developed in E7-VRP-vaccinated mice as determined by complete protection from tumor challenge 3 months after the final vaccination. These promising results highlight the potent CD8⁺ T-cell-mediated antitumor effects elicited by VEE replicon-based vectors and support their further development toward clinical testing against cervical intraepithelial neoplasia or carcinoma.

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