Therapy of Human Papillomavirus-Related Disease

Abstract

This chapter reviews the current treatment of chronic and neoplastic 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, preneoplastic lesions and some very early cancers cannot be successfully treated by surgical procedures alone. Chemoradiation therapy of cervical cancer contributes to the 66–79% 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 (~50–60%) in treatment of high grade vulvar intraepithelial neoplasia. 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 “successful” treatment is 30–40%. 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 “Opportunities for comprehensive control of HPV infections and related diseases” Vaccine Volume 30, Supplement X, 2012.

Porphyrin-based cationic amphiphilic photosensitisers as potential anticancer, antimicrobial and immunosuppressive agents

“…respiratory papillomatosis). However, although the etiology of the HPV lesions is linked to the virus, to our knowledge the PACT application has not been studied in the context of virus infection per se, but rather as a treatment of a virus-induced tumor, aiming to induce cell death and trigger immune responses in the affected area (reviewed in Lieder et al 2014;Stern et al 2012;Tao et al 2014); (2) Inhibition of viruses in blood and blood products. The transmission of bloodborne pathogens by transfusion, despite thorough screening, remains a serious problem; and it is particularly important in light of emerging infections (e.g.…”

GTL001, A Therapeutic Vaccine for Women Infected with Human Papillomavirus 16 or 18 and Normal Cervical Cytology: Results of a Phase I Clinical Trial

“…The randomized portion of the study examined the effect of GTL001 adjuvanted with topical 5% imiquimod cream. Imiquimod is a nucleoside analogue of the imidazoquinoline family that activates toll-like receptor 7 and to a lesser extent toll-like receptor 8 and is active against a variety of malignancies, including HPV-associated tumors, when applied at the tumor site (2,32). Activation of toll-like receptors by imiquimod stimulates the production of pro-inflammatory cytokines, chemokines, and other mediators, which in turn, activate antigen-presenting cells and other aspects of the innate immune system.…”

“…Although prophylactic HPV vaccines are available for preventing cervical cancer in women not yet infected with HPV, they are not effective once a woman is infected, so these women have no treatment options other than watchful waiting for clearance or, in the event that a highgrade lesion or cancer appear, surgery with possible adjunct chemotherapy (2). Surgical excision is very successful for highgrade lesions and cervical cancer, but alternatives are needed because surgery can lead to infertility, pregnancy problems, incontinence, and sexual dysfunction (2)(3)(4)(5).…”

“…A therapeutic vaccine would offer the possibility of treating HPV-infected women before local immunosuppression and viral escape mechanisms develop and high-grade lesions appear (2,6). To control existing infections and malignancies, a therapeutic vaccine should induce T-cell-mediated immunity against HPV-infected cells.…”

The role of human papillomaviruses in cancer progression

“…Therefore, therapeutic vaccines against HPV infections may play a strong role in prevention HPV associated lesions and cancers. [42] In 2006, the Food and Drug Administration approved the use of recombinant quadrivalent HPV vaccine gardasil for protection against HPV6, HPV11, HPV16 and HPV18 L1 proteins in females in the age between 9 and 26 years old. [43] It is proposed that in three doses of this vaccination at 0, 1 to 2 and 6 months, the HPV associated genital warts and the cervical cancer can be prevented.…”