Boosting the T cell response for tumor-associated antigens with mimotopes, peptide mimics of antigens, is a practical clinical strategy that does not require the identification of specific antigens for individual tumors. Clinical success employing this strategy has been promising, but inconsistent. Such approaches may be enhanced by a better understanding of the parameters of peptide/MHC binding to the TCR and the optimal T cell repertoire required for effective antitumor responses. Our overall hypothesis is that mimotopes can be designed to efficiently augment the immune response to tumors. Using a mouse tumor model system, we will determine whether increased affinity of the TCR-mimotope/MHC complex correlates with increased antitumor activity. In addition, using a new system to systematically screen a library of mimotopes of a given affinity and capacity to stimulate T cell clones, we will determine other characteristics of effective mimotopes. Specifically, we will determine whether mimotopes with either altered TCR-contact residues or with the same TCR-contact residues, but altered rotomers of the amino acid side chains that contact the TCR, are more efficient in augmenting the T cell response to tumors. Finally, we will determine whether activating a more diverse TAA-specific T cell repertoire will boost antitumor immunity. These studies will contribute to the design of new therapeutic strategies that involve stimulating the immune system to tumor antigens. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109560-05
Application #
7393729
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2004-07-09
Project End
2011-04-30
Budget Start
2008-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$269,407
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Buhrman, Jonathan D; Jordan, Kimberly R; Munson, Daniel J et al. (2013) Improving antigenic peptide vaccines for cancer immunotherapy using a dominant tumor-specific T cell receptor. J Biol Chem 288:33213-25
Buhrman, Jonathan D; Slansky, Jill E (2013) Improving T cell responses to modified peptides in tumor vaccines. Immunol Res 55:34-47
Buhrman, Jonathan D; Jordan, Kimberly R; U'ren, Lance et al. (2013) Augmenting antitumor T-cell responses to mimotope vaccination by boosting with native tumor antigens. Cancer Res 73:74-85
Franks, Alexis L; Slansky, Jill E (2012) Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res 32:1119-36
Jordan, Kimberly R; Buhrman, Jonathan D; Sprague, Jonathan et al. (2012) TCR hypervariable regions expressed by T cells that respond to effective tumor vaccines. Cancer Immunol Immunother 61:1627-38
Kemmler, Charles B; Clambey, Eric T; Kedl, Ross M et al. (2011) Elevated tumor-associated antigen expression suppresses variant peptide vaccine responses. J Immunol 187:4431-9
Jordan, Kimberly R; McMahan, Rachel H; Kemmler, Charles B et al. (2010) Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens. Proc Natl Acad Sci U S A 107:4652-7
Jordan, Kimberly R; Crawford, Fran; Kappler, John W et al. (2009) Vaccination of mice with baculovirus-infected insect cells expressing antigenic proteins. Curr Protoc Immunol Chapter 2:Unit 2.15
McWilliams, Jennifer A; Sullivan, Richard T; Jordan, Kimberly R et al. (2008) Age-dependent tolerance to an endogenous tumor-associated antigen. Vaccine 26:1863-73
Jordan, Kimberly R; McMahan, Rachel H; Oh, Jason Z et al. (2008) Baculovirus-infected insect cells expressing peptide-MHC complexes elicit protective antitumor immunity. J Immunol 180:188-97

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