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HPV and Therapeutic Vaccines: Where are We in 2010? - pdf attached
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Current Cancer Therapy Reviews May 2010
"in order to facilitate the reduction on the mortality and morbidity of HPVassociated malignancies and its precursor lesions, it is important to continue the development of therapeutic vaccines against HPV."
Barbara Ma1, Yijie Xu1, Chien-Fu Hung1,4 and T.-C. Wu1,2,3,4,*
Departments of 1Pathology, 2Obstetrics and Gynecology, 3Molecular Microbiology and Immunology, 4Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
Abstract: 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.
A. HPV and Cervical Cancer

It is now firmly established that human papillomavirus (HPV) is the etiologic agent of cervical cancer and other HPV-associated malignancies, including anogenital cancers and a subset of head and neck cancers [1]. Cervical cancer represents the second most frequent gynecological malignancy in the world, with an estimated 493,000 new cases and approximately 274,000 deaths annually [2]. Over 100 types of HPV have been identified and can be classified by their oncogenic potential. High-risk types include 16, 18, 45, 31 while low-risk types include types 6, 11 [3]. While low-risk subtypes can cause low-grade benign lesions, high-risk subtypes are connected with the development of high-grade lesions and malignant tumors. The presence of premalignant squamous intraepithelial lesions (SIL), also known as cervical intraepithelial lesions (CIN), followed by persistent infection with high-risk type HPV, is a necessary trigger of cervical cancer [1]. As HPV-16 and HPV-18 are the types most commonly associated with cervical cancer, accounting for up to 75% of all cervical cancers, they have been the focal point of preventive and therapeutic HPV vaccine development.
B. Molecular Characterization of HPV
It is essential to understand the molecular biology of human papillomavirus in order to develop HPV vaccines (for review, see [4]). HPV is a non-enveloped, double-stranded, circular DNA virus with an icosahedral capsid. Its genome is approximately 8000 base pairs long and is composed of early proteins (E1, E2, E4, E5, E6, E7) and late proteins (L1, L2). The early proteins are regulators of the viral life cycle, as they control viral DNA replication (E1 and E2), viral RNA transcription (E2), cytoskeletal reorganization (E4) and cellular transformation (E5, E6 and E7). The late proteins are structural proteins that comprise the viral capsid. In some persistent infections with high-risk HPV, HPV DNA may integrate into the host genome, resulting in the deletion of non-essential, regulatory viral genes, such as E2, E4, E5, L1 and L2. As E2 is the transcriptional repressor protein of E6 and E7, the loss of E2 leaves E6 and E7 as the principal proteins expressed within the infected cell. The E6 and E7 proteins inactivate tumor suppressors p53 and retinoblastoma (Rb) respectively and render the breakdown of cell cycle regulation. Hence, high-risk HPV-infected cells develop genomic instability, which can lead to the progression of cancer (for a review, see [5]).
C. Preventive HPV Vaccines
To block viral entry, preventive HPV vaccines aim to generate protective humoral immune responses by stimulating the production of neutralizing antibodies against L1 and/or L2 HPV viral capsid proteins. It has been shown that cells transfected with the gene encoding L1 protein are capable of assembling into HPV virus-like particles (VLPs) that are morphologically similar to native HPV virions [6, 7]. The use of VLPs to generate protective immunity against HPV infection has been demonstrated and capitalized in the development of preventive HPV vaccines [8, 9]. This progress has led to two commercially available preventive HPV vaccines - Gardasil and Cervarix. Merck?s Gardasil is a quadrivalent L1 VLP recombinant vaccine that protects against four of the most medically relevant HPV genotypes: HPV-6 and HPV-11 for benign genital warts, and HPV-16 and HPV-18 for cervical cancer. GlaxoSmithKline?s Cervarix is a bivalent L1 VLP recombinant vaccine derived from HPV types 16 and 18. They have been shown to be well tolerated, highly immunogenic, and able to induce the production of neutralizing antibodies and effectively prevent HPV-associated infection [10-12]. These vaccines, particularly Cervarix, have also exhibited partial cross-protection with other HPV types not included in the vaccine (HPV-31 and HPV-45) and hence the commercial preventive vaccines protect up to approximately 80% of cervical cancers [13].
D. Need for Therapeutic HPV Vaccines
While the successful commercialization of preventive vaccines is a significant milestone for the control of cervical cancer and possibly other HPV-associated malignancies, there is an urgent need for therapeutic HPV vaccines. First, there is a considerable population suffering from HPV infections worldwide. Since some of the HPV-associated tumor cells in which viral integration has occurred do not express detectable levels of capsid antigen (L1 and/or L2), preventive HPV vaccines are unlikely to be effective in the elimination of these HPV-associated lesions. Second, the high cost and need for appropriate storage of currently available preventive HPV vaccines may restrict their use in developing countries, which account for more than 80% of all cases of cervical cancer and have limited medical resources. Third, it is estimated that it would take approximately 20 years from the implementation of mass vaccination for preventive vaccines to impact the cervical cancer rates due to the prevalence of significant population with existing HPV infections and slow process of carcinogenesis. Thus, in order to facilitate the reduction on the mortality and morbidity of HPVassociated malignancies and its precursor lesions, it is important to continue the development of therapeutic vaccines against HPV.
In order to eliminate existing lesions, a therapeutic HPV vaccine should target HPV antigens that are continuously expressed in the infected cells and cancer cells. HPV encoded proteins E6 and E7 represent ideal targets for therapeutic intervention because of several properties. Whereas L1 and L2 are expressed only in terminally differentiated keratinocytes, HPV E6 and E7 are constitutively expressed in all levels of the epithelium of HPV-infected cells. Furthermore, because E6 and E7 are critical for the induction and maintenance of cellular transformation in HPV-infected cells, it is unlikely that the tumor cells can escape immune attack through antigen loss. In addition, since E6 and E7 are foreign proteins, immunization against HPV-associated tumors circumvents some common cancer vaccine-associated issues such as immune tolerance.
Consequently, many therapeutic vaccine strategies have focused primarily on stimulating the production and activation of T cells that can recognize infected cells expressing the target antigens E6 and E7. By delivering antigens to professional antigen-presenting cells, particularly dendritic cells (DCs), therapeutic vaccines can generate antigen-specific CD8+ T cells and CD4+ T cells (see Fig. (1)). Type 1-helper CD4+ T cells particularly are able to efficiently stimulate and augment the immune response of cytotoxic CD8+ T cells (see Fig. (2)). Together, these two arms of the adaptive immune system have the specificity and potency to kill HPV-infected cells or HPV-associated tumor cells at multiple sites in the body without inflicting significant damage on normal tissues. Different therapeutic strategies have been developed including live vector-based vaccines, peptide- or protein-based vaccines, nucleic acid-based vaccines, cellbased vaccines and combinational approaches. Table 1 sums up the advantages and disadvantages of the each approach. Table 2 summarizes the various therapeutic HPV vaccine clinical trials. This review discusses the current status of therapeutic HPV vaccines for the control of HPV-associated malignancies, with emphasis on clinical trials.

The discovery of HPV as the etiologic agent of cervical cancer has been a major driving force in the development of HPV vaccines for cancer immunotherapy. While the commercial development of preventive HPV vaccines has been hailed as a major breakthrough, the critical challenge for public health remains in implementing cost-effective HPV vaccine programs in developing countries, where women are deprived of access to effective screening and treatment programs. The next generation of preventive vaccines and new generation of therapeutic HPV vaccines must aim to be cost effective, stable for transport and storage, suitable for mass immunization, safe and highly effective in clearing existing HPV infection.
Significant progress has been made in the preclinical models, which have resulted in sevepral early phase clinical trials. However, it is important to pave the way for advanced phases of clinical trials to see the true efficacy of these vaccines. In advanced stages of cervical cancer, it is more difficult to treat with immunotherapy alone due to the potential immunosuppressive condition of patients. Therefore, the optimal approach for vaccination against cervical cancer will most likely involve the use of combinatorial strategies, including prime-boost regimens, immunomodulatory agents or other therapeutic modalities such as chemoradiotherapy and surgical debulking. Continuing progress into advanced phases of clinical trials is critical for the success of the therapeutic HPV vaccine. With ongoing advances in the development of HPV vaccines, we may some day accomplish the successful treatment of established lesions with therapeutic vaccines for the control of cervical cancer.
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