Introduction

The intent of the cervical cancer SPORE program in the next 5 years is to develop novel vaccines to improve treatment outcomes of patients with HPV-associated cervical cancer and its precursor lesions, and to better reach and protect the next generation of women from oncogenic HPV infection and its sequelae. Every year, 500,000 women are diagnosed with cervical cancer and 200,000 die from it worldwide. It is known that oncogenic human papillomaviruses (HPVs) are the primary causal agent of cervical cancer. More than 99% of cervical cancers and over 90% of their precursor lesions, squamous intraepithelial lesions (SIL), contain HPV DNA (Walboomers J.M. et al, J Pathol, 1999). A clear understanding of HPV as a necessary cause in the pathogenesis of cervical cancer has created an opportunity to control cervical cancer through both screening for and vaccination against HPV. HPV is responsible for 10% of all cancer worldwide. Historically, vaccinations have proven to be the most effective public health intervention. Therefore, this SPORE focuses on the biology of HPV in cervical cancer and its elimination through vaccination.

By identifying the precursor lesions and detecting the etiologic agent, cytologic (Pap) screening and HPV testing have provided the paradigm for molecular pathology and cancer screening programs. Cytologic screening alone has reduced the burden of cervical cancer in the US by an estimated 70%, albeit at a cost of $6 billion per annum for screening and intervention. HPV DNA testing, in conjunction with cytology, is recommended for all women over 30 years. Ultimately, it is estimated that combined cytology and HPV testing will reduce the total number of Pap smears performed annually in the US by nearly 50%, because the high negative predictive value will allow the screening interval to be lengthened to once in 3 years for women with dual negative screening tests (the majority of women > 30 years). The cost savings in a 50% reduction in the number of annual Pap smears performed in the US will be increasingly important as broad application of Gardasil ($360 per series) begins to add substantial costs to cervical cancer prevention.

The licensed HPV preventive vaccine, Gardasil represents a triumph for HPV preventive vaccine development. Gardasil is a 9-valent HPV L1 VLP recombinant vaccine produced by Merck that protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The other HPV L1 VLP vaccine, Cervarix developed by Glaxo Smith Kline contains HPV types 16 and 18, is licensed in Europe. However, Gardasil and Cervarix are unlikely to reach those who most need them. The HPV L1-based vaccines provide type-restricted protection: i.e. they protect against cervical disease relating to the HPV types included in the vaccine, but they have partial or no efficacy against other HPV types. Gardasil and Cervarix have demonstrated excellent safety profiles and are highly effective against the targeted oncogenic HPV types. Although HPV16 and 18 account for approximately 70% of cervical cancers, Gardasil and Cervarix dos not protect against all cervical cancers in unscreened populations. Since only 9 of the 15 known high-risk oncogenic HPV genotypes are targeted in these vaccines, it is important to maintain expensive, but effective cytologic screening programs. Additionally, since ~80% of cervical cancer deaths occur in developing countries that lack the resources and infrastructure for cytologic screening and intervention, vaccines need to be made available in low-resource areas to maximize the impact of vaccination on the global cervical cancer burden. Gardasil costs ~US$200 per person and it is therefore unlikely to be sustainable for low-resource areas. Even with tiered pricing, there are many other competing vaccines and health programs. Furthermore, the current HPV L1 VLP preventive vaccines must be refrigerated, which has historically proved problematic in remote and low-resource areas.

Another important obstacle for the elimination of cervical cancer is the prevalence of established HPV infections and HPV-associated disease. The existing HPV L1 VLP vaccines, Gardasil and Cervarix are not effective against pre-existing HPV infection. This is likely because infected basal epithelial cells and cervical cancers cells do not express detectable levels of capsid antigen (L1 and/or L2). This inability of preventive HPV vaccines targeting L1 and/or L2 to eliminate pre-existing infection and to eliminate HPV-related cervical cancer and precursor lesions is a serious concern since there is currently a considerable burden of HPV infections worldwide. It is estimated that it would take approximately 20 years from the implementation of mass vaccination for highly effective preventive vaccines to impact the cervical cancer rates due to the prevalence of a significant population with existing HPV infections and slow process of carcinogenesis. Furthermore, there is no available anti-viral therapy; therefore, the efficacy of current standard of care for ‘non-specific’ treatment of patients with cervical cancer is not completely effective and has significant side effects. Thus, in order to accelerate the control of cervical cancer and to treat currently infected patients with fewer side effects, it is important to develop therapeutic vaccines against HPV.

There is also a challenge of treating advanced stage cervical cancer. The current standard of care for advanced cervical cancer includes the use of a chemotherapeutic drug, cisplatin, in conjunction with local radiation therapy (Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration J Clinical Oncol, 2008). Despite improvements noted with combination therapy, five-year survival in most patients affected by advanced cervical cancer is around 35% (American Cancer Society). These treatments are also associated with significant side effects. Thus, an innovative treatment strategy that can improve outcomes with limited side effects and prolong survival in patients with advanced cervical cancer is crucially needed.

The development of novel vaccines to improve treatment outcomes of patients with persistent HPV infection, HPV-associated precancerous lesions, and cervical cancer will protect the next generation of women from oncogenic HPV infection. We have included three vaccine projects in this SPORE program based upon the success of prophylactic HPV vaccination for primary prevention of cervical cancer, and advances in understanding of cellular immunology, the impact of HIV, and vaccines in conjunction with standard chemoradiation therapy. There are three overarching goals in the SPORE: 1) Primary Prevention to reduce the global incidence of cervical cancer by improving access to prophylactic vaccination trough the development of a low cost, thermostable virus-like particle vaccine that effectively prevents infection by all oncogenic HPV types (Project 1); 2) Secondary prevention by treating HPV associated precancer lesions (Project 2) using innovative therapeutic HPV vaccines; 3) Improving Cancer Treatment by complementing existing chemoradiation and immune checkpoint blockade treatments with a therapeutic HPV vaccination (Project 3). This program is supported by an Administrative/Communication Core (Core A), a Biostatistics/Bioinformatics Core (Core B), a Tissue/Pathology/Immunology CORE (Core C), and innovates and renews through a Developmental Research Program (DRP) and a Career Enhancement Program (CEP).

Significant progress towards the development of cost-effective preventive and therapeutic vaccination strategies aimed at HPV has been made in the past several years by the team of investigators at Johns Hopkins University (JHU), the University of Alabama at Birmingham (UAB), and the University of Colorado at Boulder. These investigators with expertise in molecular and cellular biology, virology, immunology, pathology, medical and surgical oncology, and epidemiology of cervical cancer continue to work as a team with the primary long-term goal of rapidly translating scientific advances made in the laboratory into novel cost-effective preventive and therapeutic strategies to reduce cervical cancer incidence, morbidity, and mortality worldwide.

Our Vision

Our vision is that the SPORE should support translational academic research that does not readily fit in other funding categories or commercial endeavors. This is particularly important for cervical cancer, which has almost reached ‘orphan disease’ status in the US, and introduction of vaccines to low resource settings has little to attract traditional commercial entities. We thus aim to convincingly establish that the Johns Hopkins University/University of Alabama at Birmingham (JHU/UAB) Cervical Cancer SPORE grant fosters the most creative and productive use of NCI extramural funding to further the translational mission of the SPORE to reduce the cervical cancer burden. We will do this in the uniquely collaborative manner that has made the SPORE mechanism so successful and effective. This collaboration is evident by the union of the Johns Hopkins University SPORE program with the programs at UAB, and the University of Colorado to further advance the clinical development of the most promising HPV vaccines. This collaboration has also taken advantage of industrial collaborations (including Shantha Biotechnics, PaxVax, Acambis, VacTX, Dynavax, CelticPharma/Xenova/Cantab, and PowderMed/Pfizer) that are so important for rapid translation and to successfully bringing new treatments to market. We also have exploited governmental organizations such as NCI’s RAPID and RAID mechanisms, to facilitate translation. Such collaboration between multiple academic, industrial and governmental organizations is critical to the success of our program.