Applications of functional genomics to the identification of relevant human tumor antigens such as mesothelin in pancreatic and ovarian cancer provide the basis for antigen specific vaccines. However, the ultimate potency of vaccine induced antitumor immune responses is limited by preexisting tolerance, even when the targeted tumor antigen displays limited expression by normal tissues. We and others have demonstrated that amplification of immune responses in the setting of preexisting tolerance can be achieved by a) increasing costimulation and b) inhibiting the activity of Treg cells. Therefore, the major aim of this NCDDG element is to develop a costimulatory agonist and a Treg antagonist, based on gene discovery efforts within our laboratory, which will be used to amplify mesothelin-based vaccines. Recently, we discovered a new B7 family member, termed B7-DC, that is selectively expressed by dendritic cells. B7-DC can act as a strong costimulator for Th1 responses in synergy with B7.1 or B7.2. This costimulatory activity is independent of PD-1, an inhibitory receptor to which B7-DC can bind.
Aim#1 of this section will be the development and characterization of both murine and human mutant B7-DC-Fc molecules (termed B7-DC*-Fc) that have lost PD-1 binding activity but retain costimulatory activity. As part of a gene profiling project to identify Treg specific genes, we identified LAG-3 as a Treg specific cell surface molecule. In the mouse, both natural and induced Treg express increased levels of LAG-3 and antibodies to murine LAG-3 block Treg activity both in vivo and in vitro. Anti-LAG-3 monoclonal antibodies will be developed as Treg antagonists. Based on our findings that anti-LAG-3 antibodies block Treg activity in murine systems, together with the finding that tolerant T cells in various murine tumor systems express increased LAG-3, Aim#2 of this section will be to produce both murine and human anti-LAG-3 antibodies and test them for their ability to inhibit Treg cells. These agents will be combined with mesothelin-based vaccines in Sections 1 and 2 of the NCDDG.
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