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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Knoff, Jayne; Yang, Benjamin; Hung, Chien-Fu et al. (2014) Cervical Cancer: Development of Targeted Therapies Beyond Molecular Pathogenesis. Curr Obstet Gynecol Rep 3:18-32
Soong, Ruey-Shyang; Song, Liwen; Trieu, Janson et al. (2014) Toll-like receptor agonist imiquimod facilitates antigen-specific CD8+ T-cell accumulation in the genital tract leading to tumor control through IFN?. Clin Cancer Res 20:5456-67
Wu, Chao-Yi; Yang, Li-Hua; Yang, Huang-Yu et al. (2014) Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors. Clin Cancer Res 20:644-57
Soong, Ruey-Shyang; Song, Liwen; Trieu, Janson et al. (2014) Direct T cell activation via CD40 ligand generates high avidity CD8+ T cells capable of breaking immunological tolerance for the control of tumors. PLoS One 9:e93162
Yang, Ming; Yu, Tao; Wood, Joseph et al. (2014) Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model. Drug Deliv Transl Res 4:203-9
Jung, In Duk; Shin, Sung Jae; Lee, Min-Goo et al. (2014) Enhancement of tumor-specific T cell-mediated immunity in dendritic cell-based vaccines by Mycobacterium tuberculosis heat shock protein X. J Immunol 193:1233-45
Kang, Tae Heung; Knoff, Jayne; Yeh, Wei-Hsi et al. (2014) Treatment of tumors with vitamin E suppresses myeloid derived suppressor cells and enhances CD8+ T cell-mediated antitumor effects. PLoS One 9:e103562
Song, Liwen; Yang, Ming-Chieh; Knoff, Jayne et al. (2014) Cancer immunotherapy using a potent immunodominant CTL epitope. Vaccine 32:6039-48
Kang, Tae Heung; Mao, Chih-Ping; La, Victor et al. (2013) Innovative DNA vaccine to break immune tolerance against tumor self-antigen. Hum Gene Ther 24:181-8
Kang, Tae Heung; Ma, Barbara; Wang, Connie et al. (2013) Targeted coating with antigenic peptide renders tumor cells susceptible to CD8(+) T cell-mediated killing. Mol Ther 21:542-53

Showing the most recent 10 out of 71 publications