Elsevier

Vaccine

Volume 30, Supplement 5, 20 November 2012, Pages F71-F82
Vaccine

Review
Therapy of Human Papillomavirus-Related Disease

https://doi.org/10.1016/j.vaccine.2012.05.091Get rights and content

Abstract

This chapter reviews the current treatment of chronic and neoplastic human papillomavirus (HPV)-associated conditions and the development of novel therapeutic approaches. Surgical excision of HPV-associated lower genital tract neoplasia is very successful but largely depends on secondary prevention programmes for identification of disease. Only high-risk HPV-driven chronic, pre-neoplastic lesions and some very early cancers cannot be successfully treated by surgical procedures alone. Chemoradiation therapy of cervical cancer contributes to the 66ā€“79% cervical cancer survival at 5 years. Outlook for those patients with persistent or recurrent cervical cancer following treatment is very poor. Topical agents such as imiquimod (immune response modifier), cidofovir (inhibition of viral replication; induction apoptosis) or photodynamic therapy (direct damage of tumour and augmentation of anti-tumour immunity) have all shown some useful efficacy (āˆ¼50ā€“60%) in treatment of high grade vulvar intraepithelial neoplasia (VIN). Provider administered treatments of genital warts include cryotherapy, trichloracetic acid, or surgical removal which has the highest primary clearance rate. Patient applied therapies include podophyllotoxin and imiquimod. Recurrence after ā€œsuccessfulā€ treatment is 30ā€“40%. Further improvements could derive from a rational combination of current therapy with new drugs targeting molecular pathways mediated by HPV in cancer. Small molecule inhibitors targeting the DNA binding activities of HPV E1/E2 or the anti-apoptotic consequences of E6/E7 oncogenes are in preclinical development. Proteasome and histone deacetylase inhibitors, which can enhance apoptosis in HPV positive tumour cells, are being tested in early clinical trials. Chronic high-risk HPV infection/neoplasia is characterised by systemic and/or local immune suppressive regulatory or escape factors. Recently two E6/E7 vaccines have shown some clinical efficacy in high grade VIN patients and this correlated with strong and broad systemic HPV-specific T cell response and modulation of key local immune factors. Treatments that can shift the balance of immune effectors locally in combination with vaccination are now being tested.

This article forms part of a special supplement entitled ā€œComprehensive Control of HPV Infections and Related Diseasesā€ Vaccine Volume 30, Supplement 5, 2012.

Highlights

ā–ŗ Surgical excision of HPV-lower genital tract neoplasia is very successful. ā–ŗ Chemoradiation therapy of cervical cancer contributes to 66ā€“79% survival at 5yrs. ā–ŗ Improvements in treatment aim to exploit drugs or immune targeting of HPV. ā–ŗ Drugs targeting HPV action in DNA binding or apoptosis are in early development. ā–ŗ 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, āˆ¼43% of vulvar, and āˆ¼70% 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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