ZIA BC 009052 (ZIA) | |||
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Title | Papillomavirus Virion Proteins and Vaccines | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Schiller, John | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $552,447 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (5.0%) |
Anus (5.0%) Cervical Cancer (70.0%) Head and Neck (5.0%) Ovarian Cancer (4.0%) Penis (8.0%) Vaginal (5.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Vaccines |
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Abstract | |||
Papillomaviruses (PVs) infect the epithelia of animals and man, where they generally induce benign proliferation at the site of infection. However, there is a strong association between malignant progression of human genital, anal and oropharyngeal lesions and certain human papillomavirus (HPV) types, most frequently HPV 16. Our research is primarily concerned with development of vaccines and other agent to prevent and treat HPV infections and the neoplasia they induce, the elucidation of the HPV life cycle, and using the insights obtained in these studies to develop treatments against other cancers and chronic diseases. We have developed a simple and efficient strategy for generating papillomavirus-like particles (VLPs) and high titers of infectious papillomavirus particles that transduce encapsidated marker plasmids, i.e. pseudovirions. We have exploited these technologies in our basic virologic and translational research efforts. We have used our pseudovirus technology to develop the first cervicovaginal challenge model for HPVs and used this assay to define the molecular mechanism used by HPV to infect its target tissue and to determine how the antibodies induced L1- and L2-based prophylactic vaccines prevent infection. Key to the process is an obligatory binding to the heparan sulfate proteoglycans (HSPGs) on the basement membrane of a disrupted epithelium. Our development of a method to induce efficient HPV pseudovirus infection of the female genital tract after transient disruption with the over-the-counter spermicide nonoxonol-9 has proven to be the key to our recent development of an effective, and we believe practical, intravaginal vaccination strategy. We have found that intravaginal pseudovirus vaccination of N-9 treated mice induces strong systemic and mucosal T and B cell responses to target antigens transduced by the pseudovirions. Most of the induced T are long lived intraepithelial tissue resident effector memory CD8 T cells (Trms). Critically, CD8 IEL's were not induced after systemic vaccination with peptides or viral vectors. Intravaginal pseudovirus vaccination is a promising approach for focusing immune responses to the female genital tract and so should increase the effectiveness of vaccines directed against HSV infections and against HPV induced neoplasia. In collaboration with Dr. Jeff Cohen, NIAID, vectors expressing HSV antigens are were tested in mouse and guinea pig HSV-2 challenge models. Intravaginal vaccination with these vectors reduced local pathology induced by intravaginal HSV inoculation, but standard parenteral vaccination did not. In a CRADA collaborated with Crucell/Janssen, we have determined that Ad26 and Ad35 vectors induce similar locals T cell responses as intravaginal delivery of HPV pseudovirions and are superior at inducing systemic T cell responses. Crucell has extensive expertise in GMP production of their adenovirus vectors, and the company is moving our findings toward a clinical trial. To more generally evaluate the potential of HPV pseudoviruses as gene transfer vehicles, we conducted a broad infection tropism survey. In patent pending studies, we demonstrated that intact murine epithelium at all sites, whether simple, columnar, or squamous, was highly resistant to both virion binding and infection, whereas disrupted epithelium was susceptible. In contrast, virtually all human-derived carcinoma and melanoma cell lines in the NC1-60 panel were highly susceptible to VLP/psuedovirus binding/infection in vitro. The remarkable specificity of HPV VLP/pseudovirus binding and infection is mediated by specific HSPG modifications on the tumor cell surfaces that mimic those normally found on the basement membrane. The results suggest that HPV VLPs/pseudovirions may be useful in tumor diagnostic or tumor-directed cytotoxic gene or drug conjugate applications. In proof of concept studies, we documented highly specific binding and infection, and dramatic imaging, of human ovarian tumor n |