Pap screening and surgical removal of cervical intraepithelial neoplasia (CIN2/3) has greatly reduced the incidence of cervical cancer, but testing lacks precision and the LEEP/conization procedure to excise these pre-cancerous lesions is associated with cervical incompetence and premature births. Recently co-testing for high risk HPV DNAs and specifically for HPV16 in cytologic samples has been broadly implemented to improve the accuracy of screening, particularly for equivocal cytologic diagnoses, and co-testing in women of 30 or more years. Since half of all persistent HPV16 infections progress to CIN2, HPV16+ women with normal cytology (negative for intraepithelial lesion and malignancy, NILM) undergo repeat co-testing in one year per ASCCP guidelines. If HPV16+ NILM again, these women undergo colposcopy. This screening identifies large numbers of women 30 years and over with persistent HPV16 infections who are likely to eventually progress and need surgical intervention, with continued potential for transmission or the development of neoplasia at the cervix and other anogenital sites, and suffering considerable psychosocial stress. Our overall goal is to develop a regimen to safely and effectively elicit immune clearance of persistent cervical HPV16 infections for secondary prevention of cervical cancer, an important unmet medical need. Intra-muscular administration of an HPV16 E6E7L2 fusion protein (termed TA-CIN) alone had little impact on HPV16+high grade disease. Recent studies suggest that the adjuvant GPI-0100 potently enhances cellular immune responses to TA-CIN vaccination, the importance of their targeting to the disease site, and the impact of imiquimod on the local microenvironment in disease clearance. We hypothesize that local inflammation and antigen-delivery to relevant draining lymph nodes is required for effective genital tract immunity. Thus we propose to administer TA-CIN formulated with GPI-0100 adjuvant in the cervix of women with persistent HPV16 infections but normal cytology to recruit HPV-specific immune cells to the genital tract, with or without priming the local microenvironment by topical administration of imiquimod on the cervix immediately following vaccination.
Oncogenic HPV infection, notably HPV16, is the cause of 10% of cancers in women worldwide, predominantly cervical cancer. Here we are developing a treatment regimen to trigger immune clearance of persistent genital HPV16 infections before they can progress to (pre-) cancer.
|Ahn, Julie; Bishop, Justin A; Roden, Richard B S et al. (2018) The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis. Laryngoscope 128:E27-E32|
|Silver, Michelle I; Rositch, Anne F; Phelan-Emrick, Darcy F et al. (2018) Uptake of HPV testing and extended cervical cancer screening intervals following cytology alone and Pap/HPV cotesting in women aged 30-65 years. Cancer Causes Control 29:43-50|
|Yang, J-Ming; Bhattacharya, Sayak; West-Foyle, Hoku et al. (2018) Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation. Nat Commun 9:4673|
|Xing, Deyin; Zheng, Gang; Schoolmeester, John Kenneth et al. (2018) Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix. Am J Surg Pathol 42:750-760|
|Qiu, Jin; Peng, Shiwen; Ma, Ying et al. (2018) Epithelial boost enhances antigen expression by vaccinia virus for the generation of potent CD8+ T cell-mediated antitumor immunity following DNA priming vaccination. Virology 525:205-215|
|Ooki, Akira; Begum, Asma; Marchionni, Luigi et al. (2018) Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells. Int J Cancer 143:113-126|
|Leath 3rd, Charles A; Monk, Bradley J (2018) Twenty-first century cervical cancer management: A historical perspective of the gynecologic oncology group/NRG oncology over the past twenty years. Gynecol Oncol 150:391-397|
|Mao, Chih-Ping; Peng, Shiwen; Yang, Andrew et al. (2018) Programmed self-assembly of peptide-major histocompatibility complex for antigen-specific immune modulation. Proc Natl Acad Sci U S A 115:E4032-E4040|
|Wang, Joshua W; Wu, Wai Hong; Huang, Tsui-Chin et al. (2018) Roles of Fc Domain and Exudation in L2 Antibody-Mediated Protection against Human Papillomavirus. J Virol 92:|
|Bywaters, S M; Brendle, S A; Biryukov, J et al. (2018) Production and characterization of a novel HPV anti-L2 monoclonal antibody panel. Virology 524:106-113|
Showing the most recent 10 out of 291 publications