Introduction

Purpose and Intent of the Program

The intent of our program is to reduce the incidence of cervical cancer in the next 5 years and to improve the outcome in patients with HPV associated cervical cancer and their precursor lesions. Cervical cancer continues to be a major global health care problem; indeed cervical cancer remains the second leading cause of cancer death in women 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 5.2% of all cancer worldwide. Historically, vaccinations have proven the most effective public health intervention. Therefore, this SPORE is focused 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 the recently approved HPV test 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, has recently been 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 newly licensed HPV preventive vaccine, Gardasil represents a triumph for HPV preventive vaccine development. Gardasil is a quadrivalent HPV L1 VLP recombinant vaccine produced by Merck that protects against HPV types 6, 11, 16 and 18. 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. 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$360 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. Project I addresses this need with an HPV L1 capsomere vaccine specifically designed for global applicability.

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, HPV16 and HPV18. Since HPV-16 and 18 account for approximately 70% of cervical cancers, Gardasil and Cervarix may not protect against 30% of all cervical cancers in unscreened populations. Since only 2 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. Project II describes an alternative low-cost approach of an L2-based preventive vaccine that may provide very broad protection against diverse HPV types. Thus our cervical cancer SPORE program aims to develop second generation preventive HPV vaccines that will better address the global problem of cervical cancer.

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 and 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. Projects III and IV of our cervical cancer SPORE aim to develop therapeutic HPV vaccines able to eliminate pre-existing HPV-associated disease.

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) and the University of Alabama at Birmingham (UAB). 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 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, 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, and the GOG to facilitate translation. Such collaboration between multiple academic, industrial and governmental organizations is critical to the success of our program.

 

 

 

 

 

 

Copyright © 2004-2014 The Johns Hopkins University. All rights reserved.