The inability of preventive human papillomavirus (HPV) vaccines to eliminate existing HPV infections and associated lesions is a serious concern since there is a considerable burden of HPV-related cervical cancer cases worldwide. There remains a pressing need to develop therapeutic HPV vaccines to control cervical cancer. Since HPV early proteins E6 and E7 are constantly expressed in a majority of cervical cancers and are responsible for their malignant transformation, they represent ideal targets for therapeutic HPV vaccine. DNA vaccine has emerged as a promising approach to generate antigen-specific T cell immunity against E6/E7- expressing tumors or lesions. It has become apparent that the poor immunogenicity of naked DNA vaccines in patients reflects inefficient delivery of the antigenic gene to professional antigen-presenting cells, particularly dendritic cells (DCs). Thus, the challenge is to develop an approach to efficiently deliver therapeutic HPV DNA into DCs of patients to trigger cytotoxic T cell immunity, without the safety concerns related to live vectors. We have recently introduced the use of infectious papillomavirus pseudovirions as a novel approach to improve naked DNA vaccine delivery in vivo. The latest technology has enabled us to generate high titers of infectious papillomavirus pseudovirions for vaccination. Thus, infectious papillomavirus pseudovirions represent an innovative and promising delivery system for DNA vaccine to trigger potent immune responses against cancer. Specifically, we plan to Aim 1: Optimize DNA transduction of mouse keratinocytes, Langerhans cells and/or dermal DCs in mouse skin by infection with skin-tropic HPV-2/4 pseudovirions carrying a marker gene after skin barrier disruption using laser resurfacing, tape stripping or crystal microdermabrasion.
Aim 2 : Characterize the HPV-16 E6/E7-specific immune responses and antitumor effects in C57BL/6 mice infected with skin-tropic pseudovirions carrying therapeutic HPV DNA following optimized cutaneous delivery.
Aim 3 : Characterize the mechanisms of the therapeutic antitumor effects against an E6/E7-expressing tumor model in mice treated with cutaneous vaccination of skin-tropic pseudovirions carrying therapeutic HPV DNA.
Aim 4 : Characterize the combination of therapeutic HPV DNA vaccine delivered by skin-tropic pseudovirions with tumor microenvironment immune modulating factor(s) for the control of established HPV E6/E7-expressing tumors.

Public Health Relevance

Our study will create an innovative, needle-free cutaneous vaccination strategy of infection with skin-tropic papillomavirus pseudovirions carrying therapeutic HPV DNA vaccine following an optimized skin barrier-disrupting technique for the control of HPV-associated lesions. The successful implementation of our proposed study will lead to a new platform of vaccine technology that can combine the advantages of safety of DNA vaccination and efficient in vivo gene delivery mediated by viral vectors for the development of effective therapeutic vaccines for HPV and other chronic viral infections. Thus, our approach is highly significant as it may benefit a large population of individuals suffering from chronic HPV infections and HPV-associated disease all over the world and greatly advance our knowledge of immunotherapy for virus-associated tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA114425-06A1
Application #
8332907
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2005-04-08
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$303,371
Indirect Cost
$116,105
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Yang, Andrew; Farmer, Emily; Lin, John et al. (2017) The current state of therapeutic and T cell-based vaccines against human papillomaviruses. Virus Res 231:148-165
Sun, Y; Peng, S; Yang, A et al. (2017) Coinjection of IL2 DNA enhances E7-specific antitumor immunity elicited by intravaginal therapeutic HPV DNA vaccination with electroporation. Gene Ther 24:408-415
Ma, Ying; Yang, Andrew; Peng, Shiwen et al. (2017) Characterization of HPV18 E6-specific T cell responses and establishment of HPV18 E6-expressing tumor model. Vaccine 35:3850-3858
Yang, Andrew; Peng, Shiwen; Farmer, Emily et al. (2017) Enhancing antitumor immunogenicity of HPV16-E7 DNA vaccine by fusing DNA encoding E7-antigenic peptide to DNA encoding capsid protein L1 of Bovine papillomavirus. Cell Biosci 7:46
Yang, Andrew; Farmer, Emily; Wu, T C et al. (2016) Perspectives for therapeutic HPV vaccine development. J Biomed Sci 23:75
Peng, Shiwen; Qiu, Jin; Yang, Andrew et al. (2016) Optimization of heterologous DNA-prime, protein boost regimens and site of vaccination to enhance therapeutic immunity against human papillomavirus-associated disease. Cell Biosci 6:16
Sun, Yun-Yan; Peng, Shiwen; Han, Liping et al. (2016) Local HPV Recombinant Vaccinia Boost Following Priming with an HPV DNA Vaccine Enhances Local HPV-Specific CD8+ T-cell-Mediated Tumor Control in the Genital Tract. Clin Cancer Res 22:657-69
Lee, Sung Jong; Yang, Andrew; Wu, T C et al. (2016) Immunotherapy for human papillomavirus-associated disease and cervical cancer: review of clinical and translational research. J Gynecol Oncol 27:e51
Yang, Ming-Chieh; Yang, Andrew; Qiu, Jin et al. (2016) Buccal injection of synthetic HPV long peptide vaccine induces local and systemic antigen-specific CD8+ T-cell immune responses and antitumor effects without adjuvant. Cell Biosci 6:17
Yang, Andrew; Jeang, Jessica; Cheng, Kevin et al. (2016) Current state in the development of candidate therapeutic HPV vaccines. Expert Rev Vaccines 15:989-1007

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