ReviewTherapy of Human Papillomavirus-Related Disease
Highlights
āŗ Surgical excision of HPV-lower genital tract neoplasia is very successful. āŗ Chemoradiation therapy of cervical cancer contributes to 66ā79% survival at 5yrs. āŗ Improvements in treatment aim to exploit drugs or immune targeting of HPV. āŗ Drugs targeting HPV action in DNA binding or apoptosis are in early development. āŗ Modulating local and/or systemic immunity has shown some efficacy in VIN.
Introduction
In the past decade, there have been remarkable advances in our understanding of the natural history of human papillomavirus (HPV) infection and its role through persistence as the major risk factor in the development of cervical and other anogenital cancers. Primary (vaccination) or secondary (cervical screening) prevention programs can impact decisively in preventing cancer but both these approaches are not available for many at greatest risk. All those with HPV-driven chronic or neoplastic lesions and cancers potentially require therapy. If surgical removal is not possible or is unsuccessful, then other approaches are necessitated. The purpose of this chapter is to review the current treatment of chronic and neoplastic HPV-associated conditions and the prospective clinical agenda driving the development of novel therapeutic approaches. These developments exploit knowledge of the molecular virology of infection and/or neoplasia and/or the potential for stimulation of the immune response to affect viral clearance or lesion elimination or ultimately cancer therapy.
Section snippets
Lower genital tract neoplasia
Lower genital tract neoplasia comprises cervical (CIN), vaginal (VAIN), and vulvar (VIN) intraepithelial neoplasia, which in a small proportion of cases, progresses to invasive cancer. Virtually 100% of cervical, ā¼43% of vulvar, and ā¼70% of vaginal tumors are attributable to human papillomavirus infection annually generating 530,000 cervical and 21,000 vulvar and vaginal cancers worldwide ([1] and see Forman D et al., Vaccine, this issue [2]). In the absence of a screening strategy, there has
HPV specific immunotherapies
The immune system plays an important role in controlling the development of cancer [33]. The HPV genome encodes two oncoproteins, E6 and E7, which are constitutively expressed in high-grade lesions and cancer, since they are required for the onset and maintenance of the malignant cellular phenotype [34]. The presence of these defined tumor-specific antigens forms an excellent basis for the development of strategies aiming to reinforce the immune response to combat cancer. It has long been known
Immunotherapies
The challenge for immune- or antiviral-based therapies of HPV-associated conditions would be to safely provide a clear advantage over any existing treatments. For treating high grade CIN, this is likely to be extremely difficult given the current effectiveness of screening and treatment options. Nevertheless, an effective therapeutic vaccine targeting HPV16 and 18 oncogenes could provide for rapid viral clearance, prevention of latency and long-term protection against further infection relevant
Conclusion
Progress will likely come from clinical trials testing treatment of low-grade lesions of the cervix with the aim of accelerated and sustained resolution following either HPV immune or drug treatments as the stepping stone for wider therapeutic application.
Disclosed potential conflicts of interest
PLS: Has received support for Travel, Lectureships, (GlaxoSmithKline); Consultancy (GlaxoSmithKline, Oxford Biomedica); Meeting/Travel expenses (GlaxoSmithKline, Oxford Biomedica).
SHvdB: The Leiden University Medical Center (LUMC) holds a patent on the use of synthetic long peptides as vaccine (US 7.202.034). SHvdB is named as inventor on this patent. Note that the LUMC does not share the financial benefit from this patent with its employees.
INH, TB: Have disclosed no potential conflicts of
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