Research Summary
Dr. Wu’s research focuses on human papillomavirus (HPV) vaccine development.
He has created a unique preclinical murine tumor model that expresses HPV-16 oncogenic proteins (E6 and E7) and simulates specific molecular events in the progression of HPV+ precancerous lesions (CIN 3) to invasive cancer.
This model has been widely used and tested by researchers worldwide for HPV vaccine development.
Dr. Wu has focused on identifying immunotherapeutic and vaccine approaches to enhance antigen processing and presentation by dendritic cells. These include intracellular targeting and spreading strategies aimed at preventing and treating cervical lesions and cancers. Intracellular targeting directs antigens to different subcellular locations to enhance antigen processing and presentation.
Intercellular spreading helps antigens distribute to neighboring cells by taking advantage of unique intercellular transport properties that allows for an increase in the amount of antigen presented to effector cells.
Dr. Wu has created an innovative approach that combines both antigen-specific immunotherapy and anti-angiogenesis to treat HPV E7-expressing tumors.
The impressive preclinical data derived from these studies have led to several clinical trials that are either currently under way or will soon commence. The continued development of these strategies will facilitate the development of vaccines that generate a potent immune response and antitumor effect against cervical cancer.
Dr. Wu is also actively involved with investigating mechanisms of immune evasion of tumors, identifying new tumor-specific antigens and applying vaccine strategies to other cancer systems with characterized tumor-specific antigens.
Lab
The Cervical Cancer Research Lab of Drs. T-C Wu and Chien-Fu Hung has a multi-part mission to:
- Create the most effective cervical cancer vaccine for the prevention and treatment of human papillomavirus-associated malignancies
- Extend the application of the principles and strategies that we use for HPV vaccine development in order to create vaccines that target other cancers with defined tumor antigens
- Develop innovative immunological assays for human papillomavirus vaccine clinical trials
- Serve as an environment for the education of research technicians, graduate students and undergraduate students
Lab Website: Cervical Cancer Research Lab
Selected Publications
View all on PubMed
T.-C. Wu, F.G. Guarnieri, K.F. Staveley-O'Carroll, R.P. Viscidi, H.I. Levitsky, L. Hedrick, K.R. Cho, J.T. August, and D.M. Pardoll (1995) Engineering a novel pathway for MHC Class II Presentation of Antigens. Proc. Natl. Acad. Sci. 92: 11671-11675.
K.-Y. Lin, F. G. Guarnieri, K. F. Staveley-O'Carroll, H. I. Levitsky, J. T. August, D. M. Pardoll and T.-C. Wu (1996) Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Research 56:21-26.
C.-H. Chen, T.-L. Wang, C.-F. Hung, Y. Yang, H. Chen, R. A. Young, D. M. Pardoll and T.-C. Wu (2000) Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Research, 60:1035-1042.
W.-F. Cheng, C.-F. Hung, C.-Y. Chai, K.-F. Hsu, L. He, M. Ling and T.-C. Wu (2001) Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. J. Clin. Invest. 108: 669-78.
T. W. Kim, C.-F. Hung, M. Ling, J. Juang, L. He, J. M. Hardwick, S. Kumar, and T.-C. Wu (2003) Enhancing DNA vaccine potency by co-administration of DNA encoding anti-apoptotic proteins. J. Clin. Invest. 112: 109-117.
C. L. Trimble, S. Peng, F. Kos, P. Gravitt, R. Viscidi, E. Sugar, D. Pardoll, T.-C. Wu (2009) A phase I trial of a HPV DNA vaccine for HPV16+ cervical intraepithelial neoplasia 2/3. Clinical Cancer Research 15(1):361-7.
K. H. Noh, B. W. Kim, K.-H. Song, H. Cho, Y.-H. Lee, J. H. Kim, H. Cho, J.-Y. Chung, J.-H. Kim, S. M. Hewitt, S.-Y. Seong, C.-P. Mao, T-C Wu* and T. W. Kim* (2012) Nanog signaling in cancer promotes stem-like phenotype and immune evasion. J. Clin. Invest. 122: 4077-4093 * Co-corresponding authors.
T.H. Kang,CP Mao, SY Lee, A Chen, JH Lee, T.W. Kim, R Alvarez, RB Roden, D Pardoll, CF Hung, T.-C. Wu (2013). Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Research. 73(8);2493-2504.
L. Maldonado, JE Teague, MP Morrow, I. Jotova , T.-C. Wu, C. Wang, C. Desmarais, JD Boyer, B. Tycko, HS Robins, RA Clark, CL Trimble. (2014) Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci Transl Med. 29 (6) 221.
Y Sun, S Peng, J Qiu, J Miao, B Yang, J Jeang, CF Hung, T.-C. Wu (2015) Intravaginal HPV DNA vaccination with electroporation induces local CD8+ T-cell immune responses and antitumor effects against cervicovaginal tumors. Gene Therapy advance online publication. 22 (7): 528-535
Patents
DNA Vaccine Enhancement with MHC Class II Activators
Patent # US9085638 B2 | 07/21/2015
Methods for treating or preventing hyperproliferating diseases, e.g., cancer, are described. A method may comprise administering to a subject in need thereof a therapeutically effective amount of a nucleic acid encoding an MHC class I and/or II activator and optionally a nucleic acid encoding an antigen.
RNA Interference That Blocks Expression of Pro-Apoptotic Proteins Potentiates Immunity Induced by DNA and Transfected Dendritic Cell Vaccines
Patent # US9011866 B2 | 04/21/2015
An immunotherapeutic strategy is disclosed that combines antigen-encoding DNA vaccine compositions combined with siRNA directed to pro-apoptotic genes, primarily Bak and Bax, the products of which are known to lead to apoptotic death. Gene gun delivery (particle bombardment) of siRNA specific for Bak and/or Bax to antigen-expressing DCs prolongs the lives of such DCs and lead to enhanced generation of antigen-specific CD8+ T cell-mediated immune responses in vivo. Similarly, antigen-loaded DC's transfected with siRNA targeting Bak and/or Bax serve as improved immunogens and tumor immunotherapeutic agents.
Nucleic Acid Immunogenic Compositions Encoding Hsp-antigen Chimera
Patent # CA2388045 C | 02/11/2014
The invention provides chimeric nucleic acids encoding a chimeric polypeptide, constructs for expressing these polypeptides both in vitro and in vivo, isolated chimeric polypeptides, pharmaceutical compositions and methods of making and using these compositions. These compositions and methods are particularly useful for stimulating or enhancing the immunogenicity of a selected antigen or stimulating or enhancing a cellular immune response specific for that antigen. The nucleic acid of the invention comprises a first polypeptide domain comprising a carboxy terminal fragment of a heat shock protein (HSP), an Flt-3 ligand (FL), a cytoplasmic translocation domain of a Pseudomonas exotoxin A (ETA dII), or a granulocyte-macrophage-colony stimulating factor (GM-CSF) sequence, and a second polypeptide domain comprising an antigenic polypeptide.
Superior Molecular Vaccine Linking the Translocation Domain of a Bacterial Toxin to an Antigen
Patent # US8128922 B2 | 03/06/2012
Nucleic acids encoding a chimeric or fusion polypeptide which polypeptide comprises a first domain comprising a translocation polypeptide; and a second domain comprising at least one antigenic peptide are disclosed. The preferred translocation polypeptide is a bacterial toxin translocation polypeptide, such as domain II of Pseudomonas aeruginosa exotoxin A (ETA(dII)). Such nucleic acids, expression vectors thereof, and cells expressing these vectors are used as vaccine compositions in a method for enhancing an antigen specific immune response, a method of increasing the numbers of CD8+ CTLs specific for a selected desired antigen in a subject, or a method of inhibiting the growth of a tumor in a subject.
Molecular Vaccine Linking an Endoplasmic Reticulum Chaperone Polypeptide to an Antigen
Patent # US8007781 B2 | 08/30/2011
This invention provides compositions and methods for inducing and enhancing immune responses, such as antigen-specific cytotoxic T lymphocyte (CTL) responses, using chimeric molecules comprising endoplasmic reticulum chaperone polypeptides and antigenic peptides. In particular, the invention provides compositions and methods for enhancing immune responses induced by polypeptides made in vivo by administered nucleic acid, such as naked DNA or expression vectors, encoding the chimeric molecules. The invention provides a method of inhibiting the growth of a tumor in an individual. The invention also provides novel self-replicating RNA virus constructs for enhancing immune responses induced by chimeric polypeptides made in vivo.
