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Encapsulated Plasmid DNA Treatment for Human Papillomavirus 16-associated Anal Dysplasia

A Phase I Study of ZYC101¹

Department of Medicine, Division of Medical Oncology [B. K.], Departments of Stomatology [M. B., J. T., N. J., M. D. C.], Pathology [T. D.], Cancer Center [V. W., J. W.], and Laboratory Medicine [J. M. P.], University of California at San Francisco, San Francisco, California 94115, and ZYCOS, Inc., Lexington, Massachusetts 02421 [M. M., R. G. U., J. L. L., M. L. H.]

High-grade dysplasia induced by high-risk types of human papillomavirus (HPV) precedes invasive cancer in anal squamous epithelium just as it does in the cervix. A therapeutic HPV vaccine strategy as a potential treatment for anal dysplasia was tested in a standard Phase I dose escalation trial. The primary objective was to evaluate the safety of the agent; additional study aims were to evaluate the histological response, immune response, and effect on anal HPV-16 infection. Each subject was treated with four i.m. injections of 50–400 µg of ZYC101 at 3-week intervals. ZYC101 is composed of plasmid DNA encapsulated in biodegradable polymer microparticles. The plasmid DNA encodes for multiple HLA-A2-restricted epitopes derived from the HPV-16 E7 protein, one of two HPV oncoproteins consistently expressed in neoplastic cells. Fifty-six potential anal dysplasia subjects were screened to identify 12 eligible subjects with HPV-16 anal infection and a HLA-A2 haplotype. The investigational agent was well tolerated in all subjects at all dose levels tested. Three subjects experienced partial histological responses, including one of three subjects receiving the 200-µg dose and two subjects at the 400-µg dose level. Using a direct Elispot, 10 of 12 subjects demonstrated increased immune response to the peptide epitopes encoded within ZYC101; each continued to show elevated immune responses 6 months after the initiation of therapy. These results support the continued investigation of a therapeutic vaccination strategy for anal dysplasia.