Peptide antigens presented by class I MHC molecules and recognized by cytotoxic T lymphocytes (CTL) have been defined for several infectious agents and tumors of both murine and human origin. These peptides represent attractive candidates for the development of therapeutic and/or prophylactic vaccines for diseases in which CTL play an important role, including cancer. The technology for appropriate delivery of peptide antigens is still new and undergoing rapid development, and no consensus methodology exists. In addition, while CTL responses against pathogens and tumors have been stimulated by many of these methods, there have also been numerous failures. One important factor in the use of peptide antigens is that their affinity for the presenting MHC molecule will influence the level at which they are presented by APC in order to stimulate a CTL response, as well as their display on an infected cell or a tumor. In this regard, a large set of peptide antigens that are the subject of a number of clinical trials are those that have been defined as CTL targets on human melanoma cells. However, most of these peptides have a relatively low affinity for the presenting molecule HLA-A*0201, and it is not clear how to deliver these antigens in order to stimulate the most effective CTL. In addition, reproducible and generally accepted criteria for the development of effective CTL in response to vaccination are not well established. Therefore, it is important to develop means of quantifying CTL activity that bear a direct relationship to therapeutic efficacy. Comprehensive evaluation of these issues in vaccine delivery methodology in early stage clinical trials is prohibitive because of the difficulty in enrolling significant numbers of patients in many different protocols and comparing results obtained by the use of different methods. Therefore, development of appropriate preclinical models is a desirable goal.
The specific aims of this proposal will lead to the definition of methodology to measure both CTL number and avidity, and the use of this methodology to evaluate the importance of these parameters in effective tumor-specific immune responses. In addition, the impact of peptide affinity for MHC molecules on both the stimulation of CTL and their effectiveness in tumor destruction will be examined systematically. These issues will be addressed through the development of a preclinical model that will allow the evaluation of effective immune responses to peptide antigens that are presented by human class I MHC molecules.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078400-03
Application #
6173799
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Mccarthy, Susan A
Project Start
1998-09-01
Project End
2003-06-30
Budget Start
2000-07-18
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$285,712
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Engelhard, Victor H; Rodriguez, Anthony B; Mauldin, Ileana S et al. (2018) Immune Cell Infiltration and Tertiary Lymphoid Structures as Determinants of Antitumor Immunity. J Immunol 200:432-442
Rodriguez, Anthony B; Peske, J David; Engelhard, Victor H (2018) Identification and Characterization of Tertiary Lymphoid Structures in Murine Melanoma. Methods Mol Biol 1845:241-257
Woods, Amber N; Wilson, Ashley L; Srivinisan, Nithya et al. (2017) Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry. Cancer Immunol Res 5:1062-1073
Peske, J David; Thompson, Elizabeth D; Gemta, Lelisa et al. (2015) Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nat Commun 6:7114
Peske, J David; Woods, Amber B; Engelhard, Victor H (2015) Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment. Adv Cancer Res 128:263-307
Brinkman, C Colin; Rouhani, Sherin J; Srinivasan, Nithya et al. (2013) Peripheral tissue homing receptors enable T cell entry into lymph nodes and affect the anatomical distribution of memory cells. J Immunol 191:2412-25
Brinkman, C Colin; Peske, J David; Engelhard, Victor Henry (2013) Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues. Front Immunol 4:241
Thompson, Elizabeth D; Enriquez, Hilda L; Fu, Yang-Xin et al. (2010) Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J Exp Med 207:1791-804
Ferguson, Andrew R; Engelhard, Victor H (2010) CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors. J Immunol 184:4079-86
Gregg, Randal K; Nichols, Lisa; Chen, Yiming et al. (2010) Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. J Immunol 184:1909-17

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