Page 20 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 1
like particles (VLPs), encoding late HPV viral capsid proteins L1 and/or L2. T-helper cells activate B-cells to become plasma cells, which results in the generation of antibodies. These antibodies block HPV infection and induce protection from HPV. In contrast, therapeutic HPV vaccines must activate cell-mediated immunity. Antigen-presenting cells (APCs) induce priming of T-cells into effector cells. CD8+ T cells, or cytotoxic T lymphocytes (CTLs), mediate the antigen-specific killing of tumor cells and are, as such, responsible for clearance of CIN lesions. The deletion of L1 and L2 genes during HPV integration and deregulation of E6 and E7 expression in high-grade CIN renders the currently available prophylactic vaccines ineffective in targeting infected cells.[45, 46] Vaccines targeting other viral immunogens, mainly E6 and E7 oncogenes, have been developed and tested, but the development of an effective and clinically applicable therapeutic vaccine has proven challenging. The greatest challenge is the relative inaccessibility of HPV due to previously described immune evasion strategies of the virus.[44] Several different categories of vaccines have been produced and tested, which differ in the type of immunogen and delivery system. These different categories include vaccines based on bacterial vector vaccines, viral vector, peptides, proteins, DNA, RNA, dendritic cells and tumor cells.[46] DNA vaccines have emerged as the most promising form of therapeutic HPV vaccines, due to their safety, stability, manufacturability and ability to induce antigen-specific immunity.[45] However, clinical efficacy remains limited. Several phase I/II studies have shown efficacy rates of 30% to 78%.[45] One trial included a placebo group. Regression occurred in 48% of vaccinated women with CIN 2/3, compared to 30% in the placebo group (p=0.034).[47] Additional trials are ongoing, which also focus on enhancement of the vaccination effect by co-treatment with adjuvants.[44-46].
Currently, the only form of immunotherapy that is incorporated in the Dutch guideline for treatment of CIN is imiquimod cream.[7] Imiquimod enhances anti-viral and anti-tumor immunity and has been registered for treatment of genital warts and basal cell carcinoma. In the gynecological discipline, it is used to treat genital warts as well as vulvar intraepithelial neoplasia (VIN), both HPV-related diseases alike CIN. In VIN, treatment efficacy rates up to 88% have been reported.[48] Following the application in VIN, imiquimod was also studied in patients with high-grade CIN lesions. The only RCT was performed by Grimm et al., who included 59 women with high-grade CIN.[49] Disease regression and remission was more common in the imiquimod group, compared to a placebo group (73 vs 39%, p<0.05 and 47 vs 14%, p<0.05). Based on this study, treatment of high-grade CIN with imiquimod seems feasible and could reduce side effects of surgical treatment. However, despite the fact that imiquimod is incorporated in the Dutch guideline for treatment of CIN, its application in clinical practice seems limited. An important limiting factor may be a perceived lack of evidence regarding treatment efficacy. Indeed, evidence on efficacy is based on one relatively small study and long-term results in terms of recurrence rates are lacking. Clinical application of a new treatment modality warrants robust evidence of efficacy. For this reason, additional research on both short- and long-term efficacy of imiquimod for high-grade CIN seems necessary. Clinical application could also be limited by unawareness of physicians regarding imiquimod application in CIN, or unwillingness to apply it due to other reasons, such as side effects. An inventory of the awareness, attitudes and current clinical experience of gynecologists regarding imiquimod treatment of high-grade CIN could explain the limited clinical application by physicians and indicate what conditions are considered important for clinical application.
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