CD137 is an inducible molecule of the tumor necrosis factor (TNF) receptor superfamily expressed on activated T cells, NK cells and dendritic cells. Our and others' laboratories have demonstrated that CD137 agonistic monoclonal antibodies (mAb) costimulate potent cell-mediated immune responses leading to regression of established tumors in animal models. Our Iong-term goal is to elucidate the mechanisms of the CD137 mAb in immune potentiation, to maximize its therapeutic potential, and to brinq CD137 mAb-based new therapeutics to treat human cancers. We have recently found that CD137 mAb could reverse established tolerance/anergy of T cells in vivo. This may explain, at least in part, its role in overcoming tumor-induced T cell tolerance. Many human cancers express high levels of B7-H1 and/or B7-H4, which are capable of down-regulating T cell immunity. Therefore, the therapeutic effect of CD137 mAb may be compromised. In addition, we believe there are sufficient data at this time to support the development of anti-human CD137 agonistic mAb for future clinical trials of cancer therapy. In this proposal, we will elucidate the mechanisms of CD137 mAb in the reversal of tumor-induced T cell anergy and evaluate the method and approaches to overcome the roles of tumor-associated B7-H1 and B7-H4 in the evasion of tumor immunity as approaches to maximize therapeutic efficacy. Finally, we will establish """"""""humanized"""""""" CD137 mouse model using gene knock-in technology to facilitate the selection of anti-human CD137 mAb for future clinical trials. Our studies will have a direct impact on the future application of CD137 mAb in cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA106861-02
Application #
6894218
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Hecht, Toby T
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2004-05-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$335,175
Indirect Cost
Name
Johns Hopkins University
Department
Dermatology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhu, Yuwen; Yao, Sheng; Chen, Lieping (2011) Cell surface signaling molecules in the control of immune responses: a tide model. Immunity 34:466-78
Wang, Jun; Zhao, Wenxia; Cheng, Liang et al. (2010) CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice. J Immunol 185:7654-62
Narazaki, Hidehiko; Zhu, Yuwen; Luo, Liqun et al. (2010) CD137 agonist antibody prevents cancer recurrence: contribution of CD137 on both hematopoietic and nonhematopoietic cells. Blood 115:1941-8
Melero, Ignacio; Martinez-Forero, Ivan; Dubrot, Juan et al. (2009) Palettes of vaccines and immunostimulatory monoclonal antibodies for combination. Clin Cancer Res 15:1507-9
Jeong, Hye-Young; Lee, Youn-Jae; Seo, Su-Kil et al. (2008) Blocking of monocyte-associated B7-H1 (CD274) enhances HCV-specific T cell immunity in chronic hepatitis C infection. J Leukoc Biol 83:755-64
Zhu, Yuwen; Zhu, Gefeng; Luo, Liqun et al. (2007) CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype. Blood 109:4882-9
Xu, Yanhui; Tamada, Koji; Chen, Lieping (2007) LIGHT-related molecular network in the regulation of innate and adaptive immunity. Immunol Res 37:17-32
Xu, Yanhui; Flies, Andrew S; Flies, Dallas B et al. (2007) Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease. Blood 109:4097-104
Lee, Seung-Jin; Jang, Byeong-Churl; Lee, Soo-Woong et al. (2006) Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274). FEBS Lett 580:755-62
Seo, Su-Kil; Seo, Hyoun-Mi; Jeong, Hye-Young et al. (2006) Co-inhibitory role of T-cell-associated B7-H1 and B7-DC in the T-cell immune response. Immunol Lett 102:222-8