Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia: a Phase I study of ZYC101.
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 microg 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-microg dose and two subjects at the 400-microg 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.
Klencke
Barbara
B
Department of Medicine, Division of Medical Oncology, University of California at San Francisco, 94115, USA. klenckeb@medicine.ucsf.edu
Matijevic
Mark
M
Urban
Robert G
RG
Lathey
Janet L
JL
Hedley
Mary Lynne
ML
Berry
Michael
M
Thatcher
Joe
J
Weinberg
Vivian
V
Wilson
Jennifer
J
Darragh
Teresa
T
Jay
Naomi
N
Da Costa
Maria
M
Palefsky
Joel M
JM
D000328:Adult; D000368:Aged; D001005:Anus Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D004279:DNA, Viral / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004890:Erythema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D015789:HLA-A2 Antigen / Q000276:immunology; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced; D027383:Papillomaviridae / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome; D014412:Tumor Virus Infections / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D019444:Vaccines, DNA / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use
D004279:DNA, Viral; D015789:HLA-A2 Antigen; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010446:Peptide Fragments; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16