Spontaneous Regression of Grade 3 Vulvar Intraepithelial Neoplasia Associated with Human Papillomavirus-16–Specific CD4+ and CD8+ T-Cell Responses

Abstract

Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was studied in six patients affected with grade 3 vulvar intraepithelial neoplasia (VIN3, also known as bowenoid papulosis). Five of the patients presented with a chronic and persistent disease that relapsed after destructive treatments. They showed no detectable anti-HPV blood T-cell responses and no T-cell intraepidermal vulvar infiltrate containing both CD4؉ and CD8؉ lymphocytes. The last patient had a complete clearance of viral lesions, 8 months after disease onset and 2 months after electrocoagulation of <50% of the VIN3 lesions. She showed high frequency anti-E6 and anti-E7 effector blood T cells by ex vivo ELISpot-IFN␥ assay before clinical regression. Immunohistochemical study of her vulvar biopsy revealed a marked dermal infiltrate containing a majority of CD4؉ T lymphocytes and an epidermal infiltrate made up of both CD4؉ and CD8 ؉ T cells. This seems to be the first evidence of an association between spontaneous regression of VIN3 lesions and HPVspecific T-cell responses detectable in the blood. Hence, an increase of HPV-specific effector T lymphocyte responses by vaccine-based therapeutic strategies might be useful to clear the lesions in bowenoid papulosis disease.

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

“…Likewise, HPV16-induced VIN3 lesions may fail to endow the immune system with strong inflammatory signals and exogenously provided signals will be required to provide a state of inflammation. These signals can be delivered by imiquimod, electrocoagulation (50), or by vaccines (32,33,43).…”

Hepatitis B Surface Antigen-based Vaccines for Human Neoplastic Disease

“…pE7koHBE6-mediated TC-1 protection (Figure 5.3) suggested a role for E6 (EVY)-directed CTL response in pE7HBE6-immunised mice. The importance of a synergistic E6 and E7-directed CTL response may not be clear in these tumour protection experiments; however studies of natural regression of HPV lesions in women (Kadish et al, 2002;Villada et al, 2004;Trimble et al, 2005) and a murine vaccine study (Peng et al, 2006a) have demonstrated enhanced clinical benefits from a combined E6 and E7 CTL responses in control of HPVassociated tumours. Mice bearing TC-1 tumours which were treated with vaccines targeting both E6 and E7 were left with significantly lesser tumour metastases than mice treated with vaccine targeting E6 or E7 alone (Peng et al, 2006a).…”

“…Patients with responses to both E6 and E7 peptides were 4.4 times more likely to have cleared HPV infection and be CIN negative at a follow-up visit than non-responder patients. In a single patient of a separate study, E6-and E7-directed T-cell responses were associated with regression of vulvar intraepithelial neoplasia-3 lesions (VIN 3), compared to five nonresponders, who did not demonstrate regression (Villada et al, 2004). Women whose HPV-16…”

“…Furthermore, CTL responses are thought to be involved in the spontaneous regression of HPV-associated tumours and warts (Tagami et al, 1985;Aiba et al, 1986;Coleman et al, 1994;Villada et al, 2004). Therefore, to determine if pE7HBE6 could be used to treat .…”

“…Specifically, responses to E6 and E7 and patterns of CTL epitope recognition increase the likelihood of spontaneous regression of HPV-associated cervical neoplasia (Kadish et al, 1997;Nakagawa et al, 2005). Vaccines that elicit CD8 + CTLmediated protection against HPV-associated tumour have demonstrated success in animal models (Parish, 1962;Kreider, 1963;Okabayashi et al, 1991;Okabayashi et al, 1993) and early human clinical trials (Villada et al, 2004;Kenter et al, 2009). However, there remains no current vaccine to provide CTL-mediated therapy to treat HPV lesions.…”