Introduction
High-risk human papillomavirus (hrHPV) infection is responsible for approximately 5% of all human cancers, and nearly all cases of cervical cancer are initiated by persistent hrHPV infection. According to the 2020 Global Cancer Statistics,1 there are approximately 600,000 new cases of cervical cancer and 340,000 deaths worldwide annually. A large-scale epidemiological study of 138,000 Chinese women in 2020 revealed that the HPV infection rate in gynecological clinics was approximately 23.5%, of which hrHPV infection accounted for 19.4%.2 Despite the implementation of standardized cervical cancer screening, persistent hrHPV infections remain extremely common in the clinic.2-3 During persistent hrHPV infection, if the viral DNA becomes integrated into the host genome, constitutive overexpression of viral E6 and E7 oncoproteins induces the degradation of tumor suppressor p53 and pRb1, leading to cervical intraepithelial lesions and carcinogenesis.4Therefore, urgent clinical intervention is needed to eliminate persistent hrHPV infection and promote regression of HPV-associated high-grade squamous intraepithelial lesions (HSIL).
In recent years, HPV preventive vaccines have been applied clinically to prevent HPV infection; however, these vaccines do not generate strong therapeutic effects against existing HPV infections and established lesions.5 Studies have demonstrated that 99% of cervical cancers harbor the hrHPV E6 and E7 oncogenes, making the E6/E7 viral oncogene an attractive target for the development of anti-hrHPV drugs or therapeutic vaccines.6-7 The major difference between a therapeutic vaccine and a preventive vaccine is that the former confers cell-mediated immunity to kill infected cells instead of introducing neutralizing antibodies into the system. Some HPV therapeutic vaccines, such as VGX 3100, GX-188E, pNGVL4a-CRT/E7 (detox), and PepCan + Candin ADXS11-OO1, have undergone clinical trials, and some therapeutic modalities, such as genome editing and immunity therapy for E6/E7, have also been explored.8-11
REBACIN® is an innovative anti-HPV biologic. In 2010, we reported for the first time that the viral E6/E7 oncogenes were the target of REBACIN® in clearing persistent hrHPV infection.12 In vitro, REBACIN®significantly inhibited the expression of HPV E6 and E7 oncogenes in TC-1 and HeLa cells. In vivo, REBACIN® can effectively inhibit viral E6/E7-induced tumor growth in severe combined immunodeficiency disease (SCID) mice, and the experimental data in both cells and animals are shown in a dose-dependent manner.13 Our clinical studies demonstrated that REBACIN® significantly eliminates persistent hrHPV infection and promotes regression of the associated intraepithelial neoplasia.13-14 This review summarizes the progress of REBACIN® in clearing persistent hrHPV infection and promoting the regression of HPV-associated cervical precancerous lesions, with the aim of providing a new non-invasive clinical intervention option to clear persistent hrHPV infection and associated cervical lesions.