Immunotherapy that targets the human papillomavirus (HPV) E6 protein may provide an opportunity to control HPV-associated cervical malignancies. It has been established that T cell-mediated immunity is one of the most crucial components of defense against HPV-associated lesions and that dendritic cells (DCs) are the most potent professional antigen presenting cells (APCs) that prime helper and killer T cells in vivo. Furthermore, it has been shown that intradermal administration of DNA vaccines via gene gun represents an efficient means of delivering DNA vaccines into professional APCs in vivo. We have therefore used the gene gun delivery system to test strategies that require direct delivery of DNA vaccines to professional APCs. We have successfully tested several intracellular targeting strategies that enhance MHC class I and class II processing and presentation and have generated impressive results. Recently, we tested a variety of anti-apoptotic factors for their ability to enhance DC survival and antigen-specific CD8+ T cell immune responses when co-administered with DNA vaccines. Because intracellular targeting and anti-apoptotic strategies modify DCs via different mechanisms, we have been able to combine anti-apoptotic strategies for prolonging DC life with intracellular targeting strategies for enhancing MHC class I and II presentation of antigen by DCs to improve DNA vaccine potency. While coadministration of DNA encoding antigen with DNA encoding anti-apoptotic proteins can significantly enhance DNA vaccine potency, the use of DNA encoding anti-apoptotic proteins raises significant concerns related to oncogenicity. A relatively new technology, RNA interference (RNAi) using small interfering RNA (siRNA) targeting pro-apoptotic proteins may provide similar effects while alleviating concerns for oncogenicity. Thus, in the current proposal we plan to test the hypothesis that intradermal delivery of a DNA vaccine encoding HPV-16 E6 in conjunction with siRNA targeting key pro-apoptotic proteins to antigen-expressing dendritic cells would prolong transfected DC life and lead to enhanced E6-specific T cell-mediated immune responses and antitumor effects in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA114425-01
Application #
6908830
Study Section
Special Emphasis Panel (ZRG1-CII (01))
Program Officer
Welch, Anthony R
Project Start
2005-04-08
Project End
2010-03-31
Budget Start
2005-04-08
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$321,185
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Lin, Yi-Hsin; Yang, Ming-Chieh; Tseng, Ssu-Hsueh et al. (2018) Integration of Oncogenes via Sleeping Beauty as a Mouse Model of HPV16+ Oral Tumors and Immunologic Control. Cancer Immunol Res :
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; 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
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
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
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

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