A stratified randomized double-blind phase II trial of celecoxib for treating patients with cervical intraepithelial neoplasia: The potential predictive value of VEGF serum levels: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: To examine the effect of celecoxib on cervical intraepithelial neoplasia 3 (CIN 3). This is a NRG Oncology/Gynecologic Oncology Group study with translational biomarkers. PATIENTS AND METHODS: Patients with CIN 3 were randomized to celecoxib 400mg once daily (67 patients) or placebo (63 patients) for 14-18weeks. The primary outcome measure was histologic regression. A test of equal probabilities of success between two therapies was conducted, using Fisher's Exact Test at alpha=10% and 90% power when the treatment arm boosted the probability of success by 30%. Translational analysis included cervical tissue HPV genotyping, COX-2 expression in biopsies, and serum celecoxib and VEGF levels. RESULTS: In primary analysis, histologic regression was not significantly higher in the celecoxib group (40%) than in the placebo group (34.1%). However, exploratory analyses suggest patients with high serum VEGF levels exhibited greater regression in the celecoxib arm (47.3%) than in the placebo arm (14.3%). Regression rates were similar by treatment group in patients with low VEGF. VEGF levels increased over time in the placebo group, but remained the same in the treatment group. COX-2 expression in cervical biopsies declined from pre-treatment to the end of treatment with celecoxib; it did not change with placebo. CONCLUSIONS: Celecoxib at 400mg once daily for 14-18weeks did not significantly decrease the severity of CIN 3 compared with placebo except, possibly, in subjects with high baseline VEGF. Therefore, serum VEGF levels might identify patients who may benefit from celecoxib or other therapies, personalizing future chemoprevention trials for CIN 3.

Gaps and Opportunities to Improve Prevention of Human Papillomavirus-Related Cancers.

Human papillomavirus (HPV) infections cause more than 35,900 cancers annually in the United States. Although cervical cancer is the most prevalent HPV-related malignancy in women, the virus is also responsible for a significant percentage of anal, vaginal, and vulvar cancers. A comprehensive approach to mitigating cervical cancer includes HPV vaccination (primary prevention), screening and treatment of precancerous lesions (secondary prevention), and diagnosis and treatment of invasive cancer (tertiary prevention). Although a successful strategy, there are opportunities to innovate and increase access that can also be adapted to address the unique clinical care gaps that exist with the other anogenital cancers. The Society for Women's Health Research held a series of interdisciplinary meetings and events, during which expert researchers, clinicians, patient advocates, and health care policy leaders evaluated the current landscape of HPV-related cancers and their effects on women's health. This report summarizes the discussions of this working group and areas it identified in which to address gaps in primary and secondary prevention approaches to improve access and health outcomes for women with HPV-related anogenital cancers.

Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy.

It is now recognized that the immune system can be a key component of restraint and control during the neoplastic process. Human papillomavirus (HPV)-associated cancers of the anogenital tract and oropharynx represent a significant clinical problem but there is a clear opportunity for immune targeting of the viral oncogene expression that drives cancer development. However, high-risk HPV infection of the target epithelium and the expression of the E6/E7 oncogenes can lead to early compromise of the innate immune system (loss of antigen-presenting cells) facilitating viral persistence and increased risk of cancer. In these circumstances, a succession of interacting and self-reinforcing events mediated through modulation of different immune receptors, chemokine and cytokine responses (CCL20; CCL2; CCR2; IL-6; CCR7; IL-12) further promote the generation of an immune suppressive microenvironment [increased levels of Tregs, Th17, myeloid-derived suppressor cells (MDSCs) and PD-L1]. The overexpression of E6/E7 expression also compromises the ability to repair cellular DNA, leading to genomic instability, with the acquisition of genetic changes providing for the selection of advantaged cancer cells including additional strategies for immune escape. Therapeutic vaccines targeting the HPV oncogenes have shown some encouraging success in some recent early-phase clinical trials tested in patients with HPV-associated high-grade anogenital lesions. A significant hurdle to success in more advanced disease will be the local and systemic immune suppressive factors. Interventions targeting the different immunosuppressive components can provide opportunity to release existing or generate new and effective antitumour immunity. Treatments that alter the protumour inflammatory environment including toll-like receptor stimulation, inhibition of IL-6-related pathways, immune-checkpoint inhibition, direct modulation of MDSCs, Tregs and macrophages could all be useful in combination with therapeutic HPV vaccination. Future progress in delivering successful immunotherapy will depend on the configuration of treatment protocols in an insightful and timely combination.

Human papillomavirus in infants: transmission, prevalence, and persistence.

Human Papillomavirus (HPV) is very common in reproductive age women. It has been demonstrated that this infection can be transmitted from mother to infant. Evidence of HPV infection can be seen in infant and toddlers. A review of the literate was undertaken to examine the manner in which HPV can be transmitted, the rate at which transmission occurs, and if HPV can persist. The manifestations of HPV were also reviewed. It is not clear what effect the quadravalent HPV vaccine, given to mothers will have on HPV infections in infants.

Human papillomavirus vaccines--immune responses.

Prophylactic human papillomavirus (HPV) virus-like particle (VLP) vaccines are highly effective. The available evidence suggests that neutralising antibody is the mechanism of protection. However, despite the robust humoral response elicited by VLP vaccines, there is no immune correlate, no minimum level of antibody, or any other immune parameter, that predicts protection against infection or disease. The durability of the antibody response and the importance of antibody isotype, affinity and avidity for vaccine effectiveness are discussed. Once infection and disease are established, then cellular immune responses are essential to kill infected cells. These are complex processes and understanding the local mucosal immune response is a prerequisite for the rational design of therapeutic HPV vaccines. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.