This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Davidson, E. J. Articles by Stern, P. L. Search for Related Content PubMed PubMed Citation Articles by Davidson, E. J. Articles by Stern, P. L.

Immunological and Clinical Responses in Women with Vulval Intraepithelial Neoplasia Vaccinated with a Vaccinia Virus Encoding Human Papillomavirus 16/18 Oncoproteins¹

Immunology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom [P. L. S., E. J. D.]; University Department of Obstetrics and Gynaecology, St. Mary’s Hospital, Manchester, United Kingdom [E. J. D., A. E. T., R. J. M., H. C. K.]; Xenova Research, Ltd., Cambridge, United Kingdom [C. N. B., J. D., J. S. R., J. H.]; and Applied Tumor Virology, Deutsches Krebsforschungszentrum, Heidelberg, Germany [P. S., M. P.]

This study assessed the immunological and clinical responses of women with human papillomavirus (HPV) 16-associated high-grade vulval intraepithelial neoplasia (VIN) vaccinated with TA-HPV, a recombinant vaccinia virus encoding modified HPV 16 and 18 E6 and E7. Eighteen women with HPV 16-positive high-grade VIN were vaccinated with TA-HPV. The extent of their baseline disease was compared after 24 weeks by lesion measurements and histological analysis. Viral load was assessed pre- and postvaccination by real time PCR. Cell-mediated immunity to HPV 16 E6 and/or E7 peptides (HLA-A2 epitopes) or vaccinia-infected cell lysates was determined by IFN- enzyme-linked immunospot (ELISPOT) and T cell proliferation using an HPV 16 L2E6E7 fusion protein. Antibodies were measured by ELISA using vaccinia-infected cell lysates or HPV 16 and 18 E6 and E7 glutathione S-transferase-fusion proteins. Lesion-infiltrating CD4⁺, CD8⁺, CD1a⁺, and CD68⁺ immune cells were assessed by immunohistochemistry. The single vaccination with TA-HPV was well tolerated, and all patients showed an increased ELISPOT and/or antibody response to vaccinia. There were significant differences in HPV-16 E7-specific ELISPOT and L2E6E7 proliferative responses in the patients at one or more time points postvaccination as compared with the prevaccination status; two patients showed transient increased antibody responses. Overall, 13 women showed an increased HPV 16-specific immune response by one or more methodologies after immunization. Eight patients demonstrated a reduction in lesion diameter of at least 50% and a further four patients showed significant symptom relief. Viral load was reduced or cleared in six of eight lesion responders but also in six of ten nonresponders. Before vaccination, clinical responders had significantly higher levels of lesion-associated CD4⁺, CD8⁺, and CD1a⁺-immune cells than nonresponders. There were no differences in CD68 (macrophages) between responders and nonresponders before or after vaccination. Nonresponders did show a significant increase in CD4⁺- and CD8⁺- but not CD1a⁺-immune cells postvaccination but at lower levels overall than responder patients. Local immune infiltration may be a critical factor in potential responsiveness to vaccine therapy in HPV-associated neoplasia and should be carefully monitored in future placebo-controlled trials of immunotherapy for VIN.

This article has been cited by other articles:

				G. G. Kenter, M. J.P. Welters, A. R. P.M. Valentijn, M. J.G. Lowik, D. M.A. Berends-van der Meer, A. P.G. Vloon, F. Essahsah, L. M. Fathers, R. Offringa, J. W. Drijfhout, et al. Vaccination against HPV-16 Oncoproteins for Vulvar Intraepithelial Neoplasia N. Engl. J. Med., November 5, 2009; 361(19): 1838 - 1847. [Abstract] [Full Text] [PDF]

				M. van Seters, I. Beckmann, C. Heijmans-Antonissen, M. van Beurden, P. C. Ewing, F. J. Zijlstra, T. J.M. Helmerhorst, and A. KleinJan Disturbed Patterns of Immunocompetent Cells in Usual-Type Vulvar Intraepithelial Neoplasia Cancer Res., August 15, 2008; 68(16): 6617 - 6622. [Abstract] [Full Text] [PDF]

				U. Winters, S. Daayana, J. T. Lear, A. E. Tomlinson, E. Elkord, P. L. Stern, and H. C. Kitchener Clinical and Immunologic Results of a Phase II Trial of Sequential Imiquimod and Photodynamic Therapy for Vulval Intraepithelial Neoplasia Clin. Cancer Res., August 15, 2008; 14(16): 5292 - 5299. [Abstract] [Full Text] [PDF]

				S. K. Hussain, M. M. Madeleine, L. G. Johnson, Q. Du, M. Malkki, H.-W. Wilkerson, F. M. Farin, J. J. Carter, D. A. Galloway, J. R. Daling, et al. Cervical and Vulvar Cancer Risk in Relation to the Joint Effects of Cigarette Smoking and Genetic Variation in Interleukin 2 Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1790 - 1799. [Abstract] [Full Text] [PDF]

				A. Jorritsma, A. D. Bins, T. N.M. Schumacher, and J. B.A.G. Haanen Skewing the T-Cell Repertoire by Combined DNA Vaccination, Host Conditioning, and Adoptive Transfer Cancer Res., April 1, 2008; 68(7): 2455 - 2462. [Abstract] [Full Text] [PDF]

				G. G. Kenter, M. J.P. Welters, A.R. P.M. Valentijn, M. J.G. Lowik, D. M.A. Berends-van der Meer, A. P.G. Vloon, J. W. Drijfhout, A. R. Wafelman, J. Oostendorp, G. J. Fleuren, et al. Phase I Immunotherapeutic Trial with Long Peptides Spanning the E6 and E7 Sequences of High-Risk Human Papillomavirus 16 in End-Stage Cervical Cancer Patients Shows Low Toxicity and Robust Immunogenicity Clin. Cancer Res., January 1, 2008; 14(1): 169 - 177. [Abstract] [Full Text] [PDF]

				S. J. Piersma, E. S. Jordanova, M. I.E. van Poelgeest, K. M.C. Kwappenberg, J. M. van der Hulst, J. W. Drijfhout, C. J.M. Melief, G. G. Kenter, G. J. Fleuren, R. Offringa, et al. High Number of Intraepithelial CD8+ Tumor-Infiltrating Lymphocytes Is Associated with the Absence of Lymph Node Metastases in Patients with Large Early-Stage Cervical Cancer Cancer Res., January 1, 2007; 67(1): 354 - 361. [Abstract] [Full Text] [PDF]

				R. Gambhira, P. E. Gravitt, I. Bossis, P. L. Stern, R. P. Viscidi, and R. B.S. Roden Vaccination of Healthy Volunteers with Human Papillomavirus Type 16 L2E7E6 Fusion Protein Induces Serum Antibody that Neutralizes across Papillomavirus Species Cancer Res., December 1, 2006; 66(23): 11120 - 11124. [Abstract] [Full Text] [PDF]

				G. G. Grabenbauer, G. Lahmer, L. Distel, and G. Niedobitek Tumor-Infiltrating Cytotoxic T Cells but not Regulatory T Cells Predict Outcome in Anal Squamous Cell Carcinoma. Clin. Cancer Res., June 1, 2006; 12(11): 3355 - 3360. [Abstract] [Full Text] [PDF]

				A. Mahdavi and B. J. Monk Vaccines Against Human Papillomavirus and Cervical Cancer: Promises and Challenges Oncologist, August 1, 2005; 10(7): 528 - 538. [Abstract] [Full Text] [PDF]

				M. I.E. van Poelgeest, M. van Seters, M. van Beurden, K. M.C. Kwappenberg, C. Heijmans-Antonissen, J. W. Drijfhout, C. J.M. Melief, G. G. Kenter, T. J.M. Helmerhorst, R. Offringa, et al. Detection of Human Papillomavirus (HPV) 16-Specific CD4+ T-cell Immunity in Patients with Persistent HPV16-Induced Vulvar Intraepithelial Neoplasia in Relation to Clinical Impact of Imiquimod Treatment Clin. Cancer Res., July 15, 2005; 11(14): 5273 - 5280. [Abstract] [Full Text] [PDF]

				K. L. Smith, A. Tristram, K. M. Gallagher, A. N. Fiander, and S. Man Epitope specificity and longevity of a vaccine-induced human T cell response against HPV18 Int. Immunol., February 1, 2005; 17(2): 167 - 176. [Abstract] [Full Text] [PDF]

				I. B. Villada, M. M. Barracco, M. Ziol, A. Chaboissier, N. Barget, S. Berville, B. Paniel, E. Jullian, T. Clerici, B. Maillere, et al. Spontaneous Regression of Grade 3 Vulvar Intraepithelial Neoplasia Associated with Human Papillomavirus-16-Specific CD4+ and CD8+ T-Cell Responses Cancer Res., December 1, 2004; 64(23): 8761 - 8766. [Abstract] [Full Text] [PDF]

				L. J. C. Smyth, M. I. E. van Poelgeest, E. J. Davidson, K. M. C. Kwappenberg, D. Burt, P. Sehr, M. Pawlita, S. Man, J. K. Hickling, A. N. Fiander, et al. Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination Clin. Cancer Res., May 1, 2004; 10(9): 2954 - 2961. [Abstract] [Full Text] [PDF]