Once tumors are established, either in humans or animal models, most currently available anti-tumor vaccines are of limited effectiveness. Critical to the development of a T cell mediated anti-tumor immune response is the interaction between T cells and antigen presenting cells (APCs). Evidence has been accumulating from studies in non-tumor systems (allografts, auto-immune diseases and intracellular parasites) that signalling between CD40L, expressed on the surface of T cells, and CD40, found on APCs, is a crucial regulator of the ability of APCs to stimulate an effective T cell mediated immune response. CD40/CD40L signalling enhances both APC costimulatory molecule (B7.1, B7.2) expression and IL-12 secretion. Recent studies from our laboratory have shown that interference with CD40/CD40L signalling markedly inhibits the ability of 3 different tumor vaccines to stimulate an anti-tumor immune response. We propose to investigate the mechanisms underlying the CD40/CD40L pathway's crucial role in the generation of an anti-tumor immune response and to study whether enhancing this signalling will lead to more effective tumor vaccines. Specifically, our aims are as follows: (1) Determine whether intact CD40/CD40L signalling is required for both tumor vaccine induced T cell priming and activated T cell anti-tumor immune function; (2) Evaluate APC costimulatory molecule expression and cytokine expression at the tumor vaccine site in vivo in the absence or presence of intact CD40/CD40L signalling; (3) Evaluate whether Thl/Th2 polarization and suppressor activity is generated in the absence of intact CD40/CD40L signalling and (4) determine whether gene modification of tumor cells to express CD40L and the combination of GM-CSF and CD40L will abrogate tumorigenicity and/or enhance immunogenicity of tumor vaccines. We expect that these studies will form the basis for new immunotherapy clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA076612-05
Application #
6513344
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Finerty, John F
Project Start
1998-07-15
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$111,300
Indirect Cost
Name
Dartmouth College
Department
Surgery
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755