Despite the availability of potentially effective screening methods, and, more recently, the introduction of prophylactic vaccines, disease associated with human papillomavirus (HPV) remains common. On a global scale, persistent infection with HPV is the proximate cause of 10% of human malignancies, including squamous cell carcinoma of the cervix (SCCx), vagina, vulva, anus, penis, and orophar-ynx [1
]. A single genotype, HPV16, accounts for over half of all cervical malignancies [2
High grade cervical intraepithelial neoplasia (CIN2/3), the immediate precursor lesion to invasive cancer, is associated with integration of the HPV genome into the host genome, with subsequent expression of two HPV gene products, E6 and E7, which inactivate p53 and pRb, respectively. Expression of these viral, non-‘self’ proteins is functionally required to initiate and maintain the transformed phenotype [3
]. However, while all cervical squamous cancers arise from untreated CIN2/3 lesions, not all CIN2/3 progress to invasive cancer. We and others have reported that across all HPV types, approximately 35% of CIN2/3 undergo complete regression in a timeframe of 4–6 months [5
]. Lesions associated with HPV16 are less likely to undergo regression than lesions associated with other HPV types [6
]. Because it is not possible to distinguish lesions which are likely to regress from those that are not, all CIN2/3 lesions are treated by excision, or, in some cases, ablation.
As CIN2/3 is associated with functionally obligate expression of the E6 and E7 viral proteins, it represents a lesion that could be susceptible to a virus-specific immune response. To date, most translational investigations have focused on the induction of systemic HPV-specific T cell responses, in patient cohorts ranging from late-stage disease to those with early, preinvasive lesions of the genital tract (reviewed in Ref. [8
]). However, while the overall approach of eliciting measureable systemic immune recognition of HPV antigens has proven to be effective for vaccines which prevent genital mucosal HPV infection, in contrast, to date, eliciting detectable systemic T cell responses to HPV viral antigens has not been a robust predictor of clinical outcome for immune therapeutic strategies for HPV disease. Overall, the translation of therapeutic vaccines has had more limited success. This may be explained in part because vaccines tested thus far have not been suffi-ciently immunogenic in humans, and also because an effective cellular immune response must traffic specifically to the site of the lesion, and successfully access it, in order to eliminate established disease.
We report here on a prospective cohort of subjects with HPV16 + CIN2/3 who were followed on a brief, observational protocol for 15 weeks prior to standard therapeutic excision of the lesion site. In this cohort, one in four lesions underwent complete histologic regression in the study window. HPV16 E6 and E7-specific T cell responses measured in the peripheral blood were marginally detectable directly ex vivo, and did not correlate with lesion regression.