Therapeutic Vaccines for Human Papillomavirus-Associated Malignancies: History
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Contributor:
Ingrid Andrêssa de Moura
,
Anna Jéssica Duarte Silva
,
Larissa Silva de Macêdo
,
Maria da Conceição Viana Invenção
,
Mylenna Máyra Gois de Sousa
,
Antonio Carlos de Freitas

Prophylactic vaccines against human papillomavirus (HPV) have proven efficacy in those who have not been infected by the virus. As for therapeutic vaccines, they require the differentiated modulation of the immune system as both chronic infections and cancers are associated with specific immunosuppression and impairment of the immune surveillance system.

  • carries
  • cancer
  • therapeutic
  • DNA
  • RNA

1. Introduction

According to the World Health Organization (WHO), cancer-related diseases represent the world’s second leading cause of death, resulting in approximately 19.3 million new cases and approximately 10 million deaths in 2020 [1]. In addition to genetic factors and habits such as smoking, alcoholism, and poor diet, infectious diseases—especially those arising from viral infections—stand out as responsible for approximately 13% of human cancers [2].
Among viruses, the human papillomavirus (HPV), belonging to the Papillomaviridae family, is linked to squamous cell carcinomas and adenocarcinomas, and is considered the second most prevalent etiologic agent, with 5% of the global burden (approximately 690,000 new cases) [2][3]. Currently, 229 types of HPV are described by the International HPV Reference Center (www.hpvcenter.se; accessed on 1 November 2022) [4][5]. All HPVs can induce benign proliferative lesions (such as warts), but 12 genotypes (HPVs types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) are considered high-risk because they are capable of inducing malignant transformations [6]. Of these, HPV16 and HPV18 comprise the most oncogenic and prevalent types [7]. Although the distribution of these genotypes varies by geographic area [8], they represent a considerable burden worldwide, especially in developing countries.
These HPVs infect both the cutaneous and mucosal epithelium and are tissue-specific, in which different subtypes preferentially infect each tumor subsite, and there may be specific immune barriers in each microenvironment [9][10]. With a high risk of infection, approximately 80% of people will be infected with HPV at some point in their lives [11]. However, while the immune system usually clears the virus, for some people, the infection remains and can lead to precancerous changes [12]. HPV infection is a major cause of cervical, anogenital, and oropharyngeal neoplasms [13], and more recently, although less prevalently, has been associated with cases of skin cancer [14], lung [15], and esophageal adenocarcinoma (EAC) [16].
Current viral infection control strategies are based on routine screening and prophylactic vaccination, implemented as a worldwide program against low-risk genotypes and the most prevalent oncogenic types [17]. Currently, three different HPV vaccines (Cervarix®, Gardasil®, and Gardasil®-9) have been or are being used worldwide to prevent HPV-related cancers [18]. More recently, the Cecolin vaccine was licensed in China, developed against types 16 and 18 and is currently under review by the WHO [19]. HPV vaccines prevent genital warts, cervical cancer, and most HPV-related cancers, including anogenital cancers [9]. In addition, it reduces the risk of most associated throat and penile cancers [20].
However, progress towards prevention is sometimes discouraging due to the limited access to vaccination and restrictions on screening for HPV-positive malignancies, particularly in developing countries [21][22]. Furthermore, despite the high efficacy linked to a significant reduction in the rate of cervical cancer, acceptance is limited, and they do not benefit patients with established tumors [23]. Traditional treatment options for these individuals, whether in advanced or recurrent stages, include chemotherapy, surgery, and radiation therapy, which are associated with a short survival and substantial adverse effects [24]. As a result, developing therapeutic options for HPV-related malignancies is imperative. Nucleic acid vaccines are safe, quick, and easy to implement platforms capable of evoking efficient adaptive responses [25][26]. However, strategies to increase the immunogenicity of DNA vaccines, minimizing the degradation of mRNA molecules, and enable their acquisition by immune cells are commonly necessary [27]. One way to overcome this limitation is to use delivery systems that allow for the uptake of specific antigens and help modulate the immune response [28].

2. Therapeutic Vaccines for HPV-Associated Malignancies

Prophylactic vaccines aim to prevent infection by a pathogen, and thus protect the individual from future contact through immunological memory [29]. The application of prophylactic vaccines induces an adaptive immune response primarily focused on the humoral immune response [30]. This immunity is achieved through B cells, but to be successful, it requires the participation of CD4+ T cells, hence depending on effective cellular immunity [31].
Capsid proteins from different high-risk HPV strains are used in preventive HPV vaccinations to generate a neutralizing antibody response that prevents recurrent HPV infection [10]. These vaccines are based on viral capsid protein L1 virus-like particles (VLPs) produced and expressed by yeast (such as Saccharomyces cerevisiae) and baculovirus in insect cells [32]. From the spontaneous self-assembly of the L1 protein, a highly immunogenic structure similar to the native conformation of virions is formed, which is then recognized by the immune system cells, inducing the production of neutralizing antibodies [33]. For these vaccines, the significance of the humoral response is evident; nevertheless, studies suggest that B cells may also have an indirect effect in modulating immune responses against HPV-related malignancies [10]. Recent studies show that additional diagnostics and therapies targeting B cells can help predict patients with a better prognosis who would benefit from less invasive treatments [34][35]. In the study by Kim et al. (2020), for example, it was found that in HPV-associated squamous cell carcinomas, B cells improved the overall survival and were activated by radiation and PD-1 blockade. Additionally, Hladíková et al. (2019) found that tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma through cell-to-cell interactions with CD8+ T cells.
As for therapeutic vaccines, they require the differentiated modulation of the immune system as both chronic infections and cancers are associated with specific immunosuppression and impairment of the immune surveillance system [36]. This vaccine aims to eliminate the disease by increasing, modulating, or redirecting the immune response, thus forcing the immune system to recognize pathogens and abnormal cells [37][38][39]. Since the pathogenic genesis of HPV is linked to the persistent expression of oncogenic viral proteins, most of them are considered as therapeutic targets against HPV-related malignancies [23].
It is currently recognized that the oncogenic causative role of high-risk HPV types is fundamentally attributed to the action of the main viral oncoproteins, E6 and E7, which, respectively, inhibit the tumor suppressors p53 and pRB, which are involved in the development of malignancies [40]. These oncoproteins act synergistically, targeting various cellular pathways involved in regulating cell cycle control, promoting cellular immortalization, and facilitating invasion and malignant progression in the host [41]. In addition to these, the HPV E5 protein has been considered an attractive therapeutic target to prevent the progression of precancerous lesions into invasive cervical cancer since it is considered a putative oncogene that acts in the first stage of carcinogenesis, is responsible for regulating the MHC-I, and mediates immune evasion [23][42]. Oncoproteins are constitutively produced at high levels in tumor cells and are not found elsewhere in the human body, which distinguishes HPV-associated cancers [41][43]. This constitutive production makes them an excellent target for the therapeutic vaccines designed to provoke a specific antitumor response, targeting cells that express the antigens and limiting the danger of harming healthy tissue [44].
Unlike prophylactic ones, they are primarily focused on cell-mediated immunity and involve the interaction between antigen-presenting cells (APCs) and naive T cells that will become CD4+ effector cells (via MHC-II) or CD8+ (via MHC-I) [45]. CD4+ cells differentiate into helper T cells that secrete effector molecules, such as cytokines, and may act by increasing the CTL (cytotoxic T lymphocyte) immune response, activating antibody-producing B cells, and modulating regulatory or inflammatory profiles [23]. As with cancer vaccines, CD4+ and CD8+ T cells travel to the tumor site and, upon finding corresponding antigens, kill tumor cells by cytotoxicity and cytokine production [45]. Therapeutic vaccine platforms against HPV-associated cancers in clinical and preclinical stages include bacterial and viral vectors, peptides, proteins, nucleic acids, and, more recently, whole cell-based vaccines [43][46]. Most platforms consisting of attenuated or inactivated pathogens generate a sufficient signal to the immune system to produce memory cells and antibodies [47]. However, they present problems associated with safety, such as virulence reversal, limitations related to efficacy against rapidly evolving pathogens, and demand for production systems with high levels of biosafety [48]. Nucleic acid vaccines, on the other hand, are third-generation vaccines that focus on the synthesis of an antigen of interest and presentation by MHC molecules, allowing the specific induction of cellular responses, which are important in the treatment of cancer, allergies, and autoimmune diseases [49][50]. Furthermore, the production of nucleic acid-based vaccines makes them quick to develop since there is no large-scale growth of highly pathogenic organisms, reducing the cost and the risk of contamination and infection [50].

This entry is adapted from the peer-reviewed paper 10.3390/pathogens11121444

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