Encyclopedia
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects:
Oncology
|
Infectious Diseases
Human papillomavirus (HPV) is recognized as a significant risk factor for head and neck cancers worldwide, and it is the most common cause of oropharyngeal cancers in the United States. Prophylactic HPV vaccines have demonstrated effectiveness against oral infection of HPV 16 and HPV 18. There are also various strategies in development of therapeutic HPV vaccines underway.
- vaccines
- human papillomavirus
- oropharyngeal cancer
- head and neck cancers
1. Introduction
Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States and is responsible for an increased incidence of oropharyngeal squamous cell cancers (OPSCC). It is widely accepted that this subset of HPV-associated head and neck cancers differ considerably from those that are not HPV related, with major differences in pathogenesis, epidemiology, and prognosis. The p16 protein is frequently overexpressed in HPV-related OPSCC, and it often serves as a surrogate marker of HPV positivity through detection via immunohistochemistry. HPV-related OPSCC patients are frequently younger and have a distinctly improved response to treatment compared to those unrelated to HPV. Moreover, prophylactic HPV vaccines have been shown to have a strong protective effect against oral infection of HPV 16 and HPV 18, which are contributors to the vast majority of HPV-positive head and neck cancer cases worldwide.
2. Epidemiology and Biology of HPV-Related Cancers
There is strong evidence of a causal link between HPV infection and OPSCC, as the oropharynx is distinctively susceptible to HPV persistence [4,5]. Approximately 70% of patients with oropharyngeal cancer are HPV positive in the United States, with other head and neck cancer sites showing lower HPV prevalence. Analyses of demographics and risk profiles demonstrate a clear contrast between HPV-related and HPV-unrelated OPSCCs. HPV-mediated OPSCC patients are more likely to be significantly younger (<60 years old), male, and of white race [6]. A study by Gillison and colleagues examining lifetime risk factor exposures for HPV-positive versus HPV-negative HNSCC patients demonstrated that HPV-positive HNSCC patients have significantly increased number of lifetime oral sex partners as well as decreased tobacco or alcohol use, greater marijuana use, and improved dentition compared to that of HPV-negative patients [7]. These risk exposures also had a strong cumulative effect. Furthermore, tumor HPV status has been shown to be a strong prognostic factor for superior survival among OPSCC patients, whereas tobacco smoking significantly increases the risk of death [8,9].
HPVs are a family of double-stranded DNA viruses containing proteins involved in viral genome replication (E1, E2 and E4) and assembly (L1 and L2) as well as accessory proteins (E5, E6, and E7) [10]. E6 and E7 are thought to be drivers of carcinogenesis through degradation of p53 and Rb proteins, respectively [11]. The L1 and L2 proteins are structural and form capsids around the viral DNA. There are over 200 types of HPV which are classified as low or high risk according to oncogenicity. HPV types are determined by the degree of homology within the L1 (major capsid protein) gene, and distinct types are defined by differences by more than 10% of the L1 DNA sequence. HPV 16 and HPV 18 are associated with a large majority of HPV-related cancers.
3. Development and Approval of HPV Prophylactic Vaccination
The discovery of virus-like particles (VLPs) from recombinant expression of the major papillomavirus capsid protein L1 in the early 1990s paved the way for vaccine development. VLPs, which can be produced in bacteria, yeast, or insect cells, do not contain an oncogenic viral genome and are immunologically similar to native virions, and animal models consistently showed that vaccination with L1 VLP elicited titers of neutralizing antibodies that protect against viral challenge [21]. Thus far, three HPV vaccines have been introduced against up to nine HPV types and have shown promising results in protecting against HPV infection and related diseases such as genital warts and cancer. The prophylactic effect specifically for oropharyngeal cancers is assumed based on clinical evidence of its prevention of oral HPV infection and HPV-associated cellular changes, including precancerous and benign lesions [22].
As of 2009, both Cervarix, a bivalent HPV vaccine, and Gardasil, a quadrivalent HPV vaccine, have been approved and commercially available. Both are composed primarily of VLPs and were shown to induce sustained serum neutralizing antibody titers of several fold higher than that seen in natural infection [23]. Cervarix contains L1 VLPs against the most common oncogenic types, HPV 16 and 18, with an adjuvant system 04 (AS04) comprising aluminum hydroxide and monophosphoryl lipid A (MPL). As a Toll-like receptor 4 (TLR4) agonist, MPL induces high levels of antibodies [24]. Gardasil, in addition to HPV 16 and 18, also contains VLPs targeting HPV 6 and 11, which cause approximately 90% of genital warts, with an aluminum hydroxyphosphate sulfate adjuvant [25].
4. Use of HPV Prophylactic Vaccination around the World
Studies demonstrate that population effectiveness is highest in those who are vaccinated prior to first sexual contact [34]. A study by Valasoulis and colleagues investigated whether HPV prophylactic vaccination alters HPV-related biomarker expression in women with established minor cervical dysplasia [35]. They found that vaccination of patients with low-grade cytologic abnormalities led to earlier clearance of HPV 16 and HPV 18 DNA-positive infections in comparison to patients who did not receive vaccination. As such, earlier administration of the HPV vaccine appears to be associated with more effective results. A meta-analysis demonstrated the population level impact of female vaccination [36]. After 5–8 years of vaccination, the prevalence of HPV 16 and 18 among girls 13–19 years of age decreased by 83% and decreased by 66% among those aged 20–24 years. A study of over 2600 men and women aged 18–33 years found that in patients who received at least one dose of an HPV vaccine, the prevalence of oral infection with four HPV types was 88% lower than those not vaccinated [37].
5. Therapeutic HPV Vaccine
While preventative vaccines, such as the aforementioned Cervarix and Gardasil 9, have proven to be highly successful in preventing genitourinary and oropharyngeal HPV infections, there are currently no therapeutic options for patients with persistent or established HPV infections. When the HPV virus integrates into the host genome, this often results in loss of some viral genes including several early (E2, E4 and E5) and late (L1 and L2) genes. As a result, L1- or L2-specific neutralizing antibodies generated by prophylactic vaccines are no longer effective against these HPV-infected cells [43].
The E6 and E7 proteins are ideal candidates for vaccine targets for several reasons. First, they are constitutively expressed and obligate oncogene drivers of HPV-associated cancers. Second, the E6 and E7 proteins are also critical for HPV virus induction and continued integration, and thus unlikely to escape immune surveillance through antigen loss. Third, E6 and E7 are foreign proteins and thus would not likely face immune tolerance with vaccination [44].
5.1. Live Vector-Based Vaccines
Live vector-based vaccines use genetically attenuated bacterial or viral vectors that carry recombinant DNA encoding the antigen of interest into the host to elicit an immune response. This vaccine vector mimics a natural infection, are highly immunogenic, and takes advantage of the microorganism’s natural ability to infect and incorporate into a host’s genome. They are able to induce a wide range of immune responses including localized reaction and/or systemic humoral cell-mediated immunity. In pre-clinical animal models, Listeria monocytogenes (Lm)-based HPV vaccines have been found to activate both innate and adaptive immune systems [45]. Axalimogene filolisbac (AXAL or ADXS11-001) is a novel therapeutic vaccine that uses an attenuated strain of Lm fused to the non-hemolytic fragment of listeriolysin O and secretes the Lm-LLO-HPV E7 fusion protein targeting HPV-positive tumors [46].
5.2. Peptide/Protein-Based Vaccines
Peptide-based therapeutic vaccines are usually made of synthetic B- or T-cell epitopes that are recognized by their corresponding immune cells, complexed with major histocompatibility complex (MHC) I or II molecules on the surface of antigen presenting cells (APCs). This then activates CD8+ killer T cells and CD4+ helper T cells to interact with B cells to produce specific antibodies against the pathogen [49]. Peptide-based vaccines have the advantage of stability, safety and feasibility of large-scale production. However, these vaccines are in turn, poorly immunogenic and require adjuvantation. One category of peptide-based vaccines contains short peptides (<15 amino acids) that do not require additional processing by professional antigen presenting cells (APCs) and can therefore bind to MHC class 1 molecules of all nucleated cells. However, presentation without co-stimulation can lead to immune tolerance and enhanced tumor growth [50]. Therefore, synthetic long peptides (SLPs) have been developed to harbor both CD4 and CD8 T-cell epitopes but require processing and presentation by professional APCs.
5.3. Nucleic Acid-Based Vaccines
Nucleic acid-based vaccines involve delivering plasmid DNA or mRNA encoding a protein of interest into the host genome. Upon transfection into these cells, the gene of interest can then be expressed and the protein produced after gaining access to the cellular processing machinery. DNA vaccines typically consist of a bacterial plasmid containing a viral promoter, the gene of interest and a termination sequence. After injection, the DNA is taken up by muscle or skin cells. Since myocytes are not professional APCs, the elicited immune response is often weaker and less sustained. When injected intradermally, dendritic cells are professional APCs which lead to MHC class I-associated CD8+ T-cell activation. MHC class II-associated CD4+ helper T cells may also be activated if professional APCs phagocytose transfected somatic cells [56]. This is because MHC class I molecules present products of proteolysis to CD8+ T cells, while MHC class II molecules present products of lysosome degradation to stimulate CD4+ T cells. Macroautophagy therefore delivers intracellular proteins to lysosomal degradation and contributes in this way to the pool of MHC class II presented proteins.
This entry is adapted from the peer-reviewed paper 10.3390/cancers14010033
This entry is offline, you can click here to edit this entry!
