Current Cancer Therapy Reviews - Volume 6, Issue 2, 2010

The discovery of human papillomavirus (HPV) as a necessary etiological factor for cervical cancer has spurred the development of preventive and therapeutic HPV vaccines for the control of HPV-associated malignancies including cervical, vulvar, vaginal, and a subset of head and neck cancers. The commercial preventive HPV vaccines, Gardasil and Cervarix, use HPV virus-like particles to generate neutralizing antibodies against HPV major capsid protein L1. However, they do not exert therapeutic effects on existing lesions and are unlikely to have an immediate impact on the prevalence of cervical cancer due to their cost and limited availability in developing countries, which account for more than 80% of cervical cancers. Thus, there is an urgent need for therapeutic HPV vaccines. Therapeutic HPV vaccines can eliminate preexisting lesions and infections by generating cellular immunity against HPV-infected cells. HPV E6 and E7 oncoproteins represent ideal targets for therapeutic intervention because of their constitutive expression in HPV-associated tumors and their crucial role in the induction and maintenance of HPV-associated disease. This review discusses the current progress of various therapeutic HPV vaccine approaches, including live vector-based, peptide/protein-based, nucleic acid-based and cell-based vaccines targeting E6 and/or E7 antigens, and their future prospects for the control of HPV-associated malignancies.

Cervical screening based on testing for the DNA of high-risk HPV types as primary screening test detects the precursors of cervical cancers earlier than cytology. This allows longer screening intervals and results in increased effectiveness in preventing invasive cervical cancers. Data suggest that protection is similar irrespective whether sole HPV testing or HPV in conjunction with cytology are applied as primary tests. In addition, protection seems similar when directly referring all HPV positive women to colposcopy and when referring only women with abnormal cytology or persistent infection (cytological triage). On the other hand, using both tests for primary screening, and especially directly referring to colposcopy all HPV positive women, results in a strong increase of unneeded colposcopies. Therefore stand-alone HPV testing as primary test, at prolonged intervals, with cytological triage is recommendable. With this approach the positive predictive value of colposcopy is similar to that obtained with cytological screening. In younger women HPV based screening could result in large overdiagnosis of regressive lesions and should therefore be avoided. Other triage methods, based on simple HPV test repeat, viral load, p16-INK4A overexpression and testing for the HPV E6/E7 mRNA are under study. Self sampling for HPV is sensitive and specific. Among non-responders to routine screening it obtained higher compliance than regular re-invitation and allowed a relevant yield of CIN2+.

This article reviews the natural history of HPV infection covering key aspects of cell biology, virology and immunology. The oncogenic HPV lifecycle is characterised by infection in basal cells of anogenital epithelia with virus production dependent on epithelial differentiation and virions produced only in terminally differentiated cells. Natural control of an oncogenic type HPV infection depends on appropriate activation of innate immune mechanisms leading to stimulation of adaptive immunity in the form of specific T cells against viral proteins such as E2, E6 and E7 which can effect clearance of the virally infected cells. Neutralising antibodies are detected in about 50% of women who have cleared such infections but are not necessarily protective against future infection by the same HPV type and are never therapeutic. In addition, the stealthy lifecycle of the virus which causes little or damage and no viraemia as well as various viral immune evasion strategies sometimes allows the virus to avoid immune detection providing for persistent infection which is the major risk factor for development of intraepithelial neoplasia. Oncogenic HPV infection is necessary but insufficient for development of a cervical cancer and additional genetic changes are acquired over time through selection including those that allow for immune escape from immune surveillance.

About 35 years ago human papillomaviruses (HPV) have been suggested as causative agent for cervical cancer whose infectious etiology had been suggested already many years before. The discovery of the plurality of HPVs encompassing a variety of types with particular biologic properties, the regular presence of the genomes of the so called high-risk types within tumor biopsies, the awareness about the transforming potential of the viral proteins and informative epidemiological surveys led to the consenting view of a causative link between these viruses and cervical cancer and ultimately triggered the development of HPV-specific vaccines for prevention of cervical cancer.

Prophyllactic HPV vaccines are efficacious in preventing persistent infections by vaccine-HPV types and related cervical disease. The maximum effect is achieved in women who are not exposed to HPV vaccine types at the time of vaccination (HPV DNA negative women). Today's published data demonstrate equal clinical vaccine efficacy in women between 15 and 26 years and women between 24 and 45 years. The public health effect of vaccinating women older than 25 years is not clear yet, but may be smaller than after vaccination of adolescents. Unresolved issues are duration of protection and long-term preventive effects after treatment of HPV-related disease or natural clearance of HPV infection. Furthermore, it remains difficult to define subgroups of older women who would benefit from the vaccine. It may be that older women exposed to HPV or who are being treated for HPV related disease will benefit most at long term. This needs longer follow-up of vaccinated women and more detailed analysis of data from vaccine trials.

New vaccine technology has led to vaccines containing highly purified antigens with improved safety profiles, but increased antigen purity often results in weakened immunogenicity. A better understanding of innate and adaptive immunity and their interaction at the molecular level has led to the use of innovative adjuvants combined with careful antigen selection. Adjuvants can be used to amplify the immune response, and the combination of antigens with more than one adjuvant, the Adjuvant System approach, allows the development of vaccines which generate specific and effective immune responses adapted to both the pathogen and the target population. One of those Adjuvant Systems is AS04, a combination of the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. The added value of MPL in AS04-based formulation above Aluminium was evidenced for a prophylactic human papillomavirus (HPV)-16/18 vaccine by higher vaccine-elicited antibody responses, as well as the induction of higher levels of memory B-cells. This review focuses on the role of AS04 for development of Cervarix™, a vaccine for the prevention of cervical cancer.

Persistent human Papillomavirus (HPV) infections are now recognised as the leading cause of cervical cancer (CC). Approximately 100 types of human infecting HPV exist in nature and according to the samples collected from either pre-cancerous or cancerous lesions, almost ten are responsible for a good part of the CC cases. Two anti-HPV vaccines are currently registered worldwide - a tetravalent and a bivalent one - for which evidences of protecting effectiveness and safety have been delivered by controlled clinical trials and clinical practice. Consequently, and as a first step, several countries implemented HPV mass vaccination programmes for girls before the age of sexual debut. Moreover, and specifically for the bivalent vaccine, efficacy over various oncogenic types has been demonstrated in a broad population also including sexually active women that had potentially already acquired an HPV infection. The opportunity to extend the primary prevention to other cohorts of women up to the adult age through the use of the vaccine, improves the possibility to actively reduce the total number of CC cases. Based on two country examples, Italy and Belgium, different strategies for HPV vaccination of pre-adolescents, adolescents and young adults are discussed.

Colorectal cancer is a leading cause of death by cancer in the western world. Present oncological treatments have relatively little impact on long term survival and hope is pinned on screening. Current population-based screening methods are insufficient in reducing colorectal cancer deaths, therefore new approaches are needed. One approach is chemoprevention, which targets specific signalling pathways to interfere in the process of carcinogenesis. However, it is of great importance to critically assess the benefits of chemoprevention in comparison to its risk and inconvenience. It is unlikely that chemoprevention can be used in a wide unselected population, but is more favourable in high risk groups such as individuals especially susceptible to neoplasia because of environmental risk factors, patients with inflammatory bowel disease, those with a hereditary predisposition to CRC (FAP, Lynch, HNPCC) and patients with a previous history of colorectal cancer or adenomatous polyps. CRC is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. Both prevention and therapy needs to be tailored to the molecular subtype of the cancer in question. This review summarises the evidence for the chemopreventive efficacy of the major agents investigated to date and their proposed molecular mechanism(s) of action.

MicroRNAs (miRNAs) are short (∼22 nucleotides), highly conserved non-coding RNA molecules that bind to sequences in the 3' untranslated region (3' UTR) of genes with full or partial complementarity, leading to their degradation and/or translational inhibition. Dysregulation of miRNA expression is associated with several human cancers and accumulation of these molecules differs significantly between normal and neoplastic cells. Several miRNAs act as oncogenes by inhibiting tumor suppressors and are over-expressed in cancers, whereas others function as tumor suppressors by inhibiting oncogenes, and are down-regulated or lost in cancers. Moreover, many miRNAs regulate multiple genes associated with one or more cancer pathways, acting as “master switches”, making them ideal targets for the treatment of this disease. Modified RNA molecules that resist nuclease degradation and mimic miRNAs or inactivate them through binding with strong affinity inhibit cancer growth and progression in animal models. The success of repressing neoplastic growth by targeting miRNAs in vivo provides an exciting prospect of using these molecules in cancer therapeutics. Here we review the current data on the involvement of miRNAs in cancer, their mechanism of action and role as “master switches”. In this review, we also discuss the prospect of targeting these “master switches” in therapeutic intervention of this disease, highlighting miRNA-based successful cancer therapy in preclinical animal models and its challenges. We finally conclude by discussing the potential of using dietary agents to modulate expression of miRNAs in cancer.

The use of cancer vaccines to induce anti-tumor immune responses holds huge potential to complement traditional cancer therapies. Cancer vaccines are designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control to the benefit of the cancer patient. Additionally, the highly specific character of the host immune response minimizes the risk for unattractive adverse effects associated with most other cancer therapies in use today. It is now well recognized that the immune system is in fact capable of recognizing spontaneous cancers. Thus, even in the absence of treatment, cells of the immune system in the cancer patients specifically recognize cancer cells. This review will focus on various strategic considerations in the development of therapeutic cancer vaccines. We will especially address the following five aspects of therapeutic vaccination against cancer: 1) Targets that elicit immune responses against tumors with the focus on proteins that are essential for function, survival and growth of cancer cells. 2) Adjuvants that enhance the efficiency of cancer vaccines either by eliciting cellular or humoral immunity. 3) The activation of appropriate immune responses in patients. Various effector mechanisms of both the innate and the adoptive immune system contribute to effective eradication of cancer cells in many different ways. 4) Combination therapy. Therapeutic vaccination can be combined with standard as well as experimental therapies, such as chemotherapy and adoptive immunotherapy, with synergistic effect. 5) Commercial cancer vaccines in clinical phase III testing. The results of several clinical phase II and III studies leaves little doubt that cancer vaccines will be part of standard anticancer treatment in the future. However, several challenges remain to explore the full potential of therapeutic vaccination against cancer.