Cervical cancer is the fourth most common cancer in women worldwide, with an annual incidence of 528,000 cases and mortality of 266,000 cases, and it is almost always caused by human papillomavirus (HPV). HPV causes not only cervical cancer but also anal, oropharyngeal, penile, vaginal, and vulvar cancers; it is estimated to be responsible for 5.2% of cancer cases worldwide. Although numerous preclinical and clinical trials have evaluated prophylactic HPV vaccines during the past few decades, these vaccines do not help those who already have established HPV infections. Therefore, therapeutic vaccines are needed for patients in which HPV infection is already established and in which HPV-related diseases have already developed.
We have developed an HPV therapeutic vaccine—PepCan—that consists of four synthetic peptides covering the E6 protein of HPV type 16 (HPV 16), along with a Candida skin-test reagent as a novel vaccine adjuvant. This combination is designed to boost anti-HPV E6 responses, which have been associated with HPV clearance and regression of cervical lesions. The four peptides were chosen to keep the most immunogenic regions (i.e., E6 46–70 and E6 91–115) intact. These four peptides have also been shown to have maturation effects on Langerhans cells (LCs), the main antigen-presenting cells in skin.
The most widely used adjuvant in approved human vaccines is an alum-based adjuvant that elicits a predominantly Th2 immune response. However, the alum-based adjuvant would not be useful in a vaccine designed to stimulate cellular immune responses. Because successful clearance of HPV infection is believed to be induced by cell-mediated immunity, an adjuvant that would promote such an immunity is necessary. The adjuvant chosen for PepCan is Candin, a colorless extract of Candida albicans that functions as a recall antigen. We have demonstrated that Candin has T-cell proliferative effects and that the cytokine most frequently produced by Langerhans cells (LCs) exposed to Candin, with and without vaccine peptides, was interleukin (IL)-12, which promotes T-cell response.
PepCan has been evaluated in a Phase I dose-escalation clinical trial treating women with biopsy-confirmed high-grade squamous intraepithelial lesions (HSILs). The vaccine was demonstrated to be safe, and the greatest histological regression was observed in the lowest-dose group 3 months after the last injection. A Phase II study will be initiated in December 2015 to evaluate the clinically optimal dose of vaccine and assess response up to 12 months post treatment.