We have identified two co-inhibitory molecules of the B7 family, B7-H1 and B7-H4, which inhibit T cell responses in an antigen-dependent fashion. The inhibitory effect of B7-H1 is mediated, at least in part, through the PD-1 receptor, and BTLA is also a putative receptor for B7-H4. Preliminary data from our laboratory and others demonstrate that B7-H1 and B7-H4, upon interaction with their counter-receptors on T cells, constitutes essential immunologic checkpoints in the down-regulation of effector T cell responses to antigens. Importantly, both B7-H1 and B7-H4 are broadly expressed on human cancers and are implicated in the suppression of T cell responses in the tumor's micro-environment. The central hypothesis of this proposal is that B7-H1 and B7-H4 are critical components within the tumor micro-environment to counterattack effector T cells through their co-inhibitory receptors. Blockade of these co-inhibitory receptors should protect tumor antigen-specific effector T cells from immune suppression, leading to potentiation of therapeutic tumor immunity. To test this, we will evaluate immune stimulatory effects of antagonist mAb to B7-H1 and B7-H4 in mouse pancreas and ovarian cancer models. Combinatorial approaches to integrate cancer vaccines, co-stimulation, and manipulation of regulatory T cells, will be explored. Furthermore, we will develop and characterize antagonist mAb to human B7-H1 and B7-H4 in xenograft models of human pancreas and ovarian cancers. Finally, new antagonist mAb will also be developed to block the inhibitory receptor PD-1 and BTLA-4 as complementary approaches to maximize therapeutic efficacy. We anticipate that these studies will provide a foundation for immediate translation of these biologies and approaches into new clinical trials of immunotherapy for pancreas and ovarian cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA113341-05
Application #
7816976
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$234,891
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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