Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination

• Published in: Clinical cancer research 2004-05, Vol.10 (9), p.2954-2961
• Main Authors: SMYTH, Lucy J. C, VAN POELGEEST, Mariëtte I. E, TRISTRAM, Amanda, KITCHENER, Henry C, OFFRINGA, Rienk, STERN, Peter L, VAN DER BURG, Sjoerd H, DAVIDSON, Emma J, KWAPPENBERG, Kitty M. C, BURT, Debbie, SEHR, Peter, PAWLITA, Michael, MAN, Stephen, HICKLING, Julian K, FIANDER, Alison N
• Format: Article
• Language: English
• Subjects: Antibodies, Viral - blood; Antineoplastic agents; Anus Neoplasms - immunology; Anus Neoplasms - prevention & control; Biological and medical sciences; Cell Division - immunology; Enzyme-Linked Immunosorbent Assay; Female; Genital Neoplasms, Female - immunology; Genital Neoplasms, Female - prevention & control; Humans; Interferon-gamma - blood; Medical sciences; Oncogene Proteins, Viral - immunology; Papillomaviridae - immunology; Papillomavirus E7 Proteins; Papillomavirus Infections - immunology; Papillomavirus Infections - prevention & control; Pharmacology. Drug treatments; Repressor Proteins - immunology; T-Lymphocytes - immunology; Time Factors; Tumors; Viral Vaccines - administration & dosage; Viral Vaccines - immunology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-03-0703

Purpose: The purpose is to study the immunogenicity of heterologous prime-boost human papillomavirus (HPV) oncogene vaccination in patients with anogenital intraepithelial neoplasia (AGIN). Experimental Design: Twenty-nine women with high-grade AGIN received three i.m. doses of TA-CIN (HPV-16 L2/E6/E7 protein) at four weekly intervals followed by a single dermal scarification of vaccinia HPV-16/18 E6/E7 and were followed up for 12 weeks. Immunity to HPV-16 was assessed by lymphoproliferation, IFN-γ enzyme-linked immunospot (ELISPOT), and ELISA. Results: The patient group significantly responded to TA-CIN and not to the control antigen HPV-6 L2/E7 at all postvaccination time points when compared with baseline responses ( P ≤ 0.05). Ten of the patients showed at least a 3-fold increase in TA-CIN-specific proliferation at one or more time points after vaccination. Comparison of stimulation with HPV-16 E6- or E7-GST fusion proteins showed that proliferative responses were biased to HPV-16 E6. This bias was also seen by IFN-γ ELISPOT using overlapping peptides, with HPV-16 E6- or E7-specific T cells being detected in 9 and 2 patients, respectively. In addition, vaccination resulted in the induction of antibodies against the HPV-16 oncoproteins. Of the 6 clinical responders, 2 patients showed both a proliferative TA-CIN-specific response and an E6-specific IFN-γ response, whereas 3 other patients displayed E6-specific reactivity only. Stable disease was recorded in 19 patients, 8 of whom showed a concomitant TA-CIN-specific proliferative and/or E6-specific T-cell response. Of the 4 progressors, 2 failed to make a T-cell response and 2 responded by either proliferation or E6 ELISPOT alone. Conclusions: The prime-boost regimen is immunogenic in AGIN patients (humoral and cellular immunity), but there is no simple relationship between induction of systemic HPV-16-specific immunity and clinical outcome. Other factors that may play a role in the eradication of long-term established AGIN lesions need to be determined to identify the patient group that would benefit from immunotherapy with the vaccines used in this study.