Polynucleotide vaccines have shown efficacy in multiple animal models, have proven safe and well-tolerated in initial clinical trials, and exhibit several practical advantages as compared to either protein or recombinant virus vaccines. However, in the case of tumor-associated """"""""self"""""""" antigens, plasmid DNA vaccines encoding tumor antigens alone generally have been no more effective than conventional protein vaccines. Recent advances in understanding factors that modulate antigen-specific immune responses, especially those promoting MHC class I-restricted antigen- specific CD8+ CTL, suggest a variety of strategies to enhance hot immune responses to """"""""self"""""""" antigens. This proposal will test the hypothesis that novel strategies can be used to augment the efficacy of polynucleotide vaccines targeting a well-studied human tumor antigen (CEA) with relevance for breast cancer. Specifically, the proposed studies will develop and test polynucleotide formulations designed to (1) prolong polynucleotide-encoded antigen expression by sustained release matrices, (2) target tumor antigen for efficient processing by antigen-presenting cells (APC) via polynucleotide vectors encoding three CEA fusion proteins, (3) recruit and activate APC and/or T cells for augmented immune responses to tumor antigen by co- delivery of polynucleotide vectors separately encoding CEA and six immune activators, and (4) enhance innate host immune """"""""danger"""""""" signals by Sindbis virus-derived replicative RNA vectors encoding CEA. Preclinical evaluation of each strategy's ability to elicit CEA-specific Th1 immune responses, CD8+ CTL and tumor protection will employ a human CEA-transgenic mouse tumor model. The strategy or combination of strategies judged to optimally augment anti-tumor immunity in mice will be selected for translation to a phase Ib clinical trial in patients with hormone-responsive, CEA-positive metastatic breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA089019-01
Application #
6403844
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2000-09-30
Project End
2005-09-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Wielgos, Monica E; Zhang, Zhuo; Rajbhandari, Rajani et al. (2018) Trastuzumab-Resistant HER2+ Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition. Mol Cancer Ther 17:921-930
Wielgos, Monica E; Rajbhandari, Rajani; Cooper, Tiffiny S et al. (2017) Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors. Mol Cancer Res 15:340-347
Forero, Andres; Li, Yufeng; Chen, Dongquan et al. (2016) Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes. Cancer Immunol Res 4:390-9
McNally, Lacey R; Mezera, Megan; Morgan, Desiree E et al. (2016) Current and Emerging Clinical Applications of Multispectral Optoacoustic Tomography (MSOT) in Oncology. Clin Cancer Res 22:3432-9
Atherton, Daniel S; Sexton, Katherine C; Otali, Dennis et al. (2016) Factors Affecting the Use of Human Tissues in Biomedical Research: Implications in the Design and Operation of a Biorepository. Methods Mol Biol 1381:1-38
Li, Rong; Zhang, Kui; Penedo, Thuy Linh et al. (2016) The RANK Pathway in Advanced Breast Cancer: Does Src Play a Role? Appl Immunohistochem Mol Morphol 24:42-50
Walters, Beth; Thompson, Sunnie R (2016) Cap-Independent Translational Control of Carcinogenesis. Front Oncol 6:128
Wu, Lizhi; Chaudhary, Sandeep C; Atigadda, Venkatram R et al. (2016) Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis. PLoS One 11:e0153556
Otali, D; Fredenburgh, J; Oelschlager, D K et al. (2016) A standard tissue as a control for histochemical and immunohistochemical staining. Biotech Histochem 91:309-26
Hoyt, Kenneth; Umphrey, Heidi; Lockhart, Mark et al. (2015) Ultrasound imaging of breast tumor perfusion and neovascular morphology. Ultrasound Med Biol 41:2292-302

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