Harnessing the power of body's immune system to prevent and treat cancers is a highly attractive approach, which can potentially substitute the highly invasive surgery, radiation and chemotherapy methods. However, the development of vaccines against cancer is an immensely challenging task due to the low immunogenicity of tumor associated carbohydrate and peptide antigens. It is crucial that new vaccine strategies and new methods of antigen delivery can be developed to train the immune system to efficiently recognize tumor antigens and mount an effective immune response. In this proposal, virus like particles (VLPs) will be examined as a new antigen delivery platform to elicit powerful anti-cancer immune responses. The central hypothesis is that highly organized display of tumor associated carbohydrate antigens (TACAs) on the self-assembled VLP surface will greatly enhance the humoral responses to the TACAs.
In aim 1, Cowpea Mosaic Virus (CPMV) VLP will be developed as a carrier to boost the immune responses to TACAs. Promising preliminary results have been obtained where high titers of specific antibodies were elicited against TACAs using CPMV as the carrier. The antibodies generated not only recognized the antigen displayed on cancer cells but also delayed tumor growth in a mouse tumor model. The CPMV constructs will be systematically varied to determine the effects of linker type, epitope density, display patterns and adjuvants on immune responses.
In aim 2, another promising VLP bacteriophage Qb will be studied as the carrier for TACAs. The availability of multiple VLPs will enable the development of a heterologous prime-boost strategy, where the humoral responses will be directed to focus on the TACA epitopes with reduced anti-carrier responses.
In aim 3, TACA, T cell epitopes and an adjuvant will be incorporated onto one VLP construct. This can not only engage the humoral arm of the immune systems, but also activate the cellular immunity simultaneously. This multi-component construct will be evaluated in both immuno-therapeutic and immune-protective settings using mouse tumor models. The comprehensive immune response generated can potentially be much more potent towards eradicating the tumor. The proposed studies will not only greatly enhance the basic understanding of the effects of antigen density, antigen patterning, and linkers on immune responses but also provide valuable pre- clinical information for future clinical evaluation of anti-cancer vaccines.

Public Health Relevance

Cancer is a major cause of mortality in the world. In this project, novel vaccine delivery systems will be developed to induce strong and comprehensive immune responses against tumor, which can greatly enhance our knowledge on effective anti-cancer vaccine constructs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149451-03
Application #
8403832
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Welch, Anthony R
Project Start
2011-01-15
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$447,677
Indirect Cost
$64,511
Name
Michigan State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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