A key component to enhance immune-based strategies in cancer-bearing individuals is to increase the survival of effector T cells specific for tumor Ag(s), which leads to increased tumor-specific memory. In cancer-bearing hosts it is important to maintain high levels of tumor Ag-specific T cells, because it is difficult to eliminate every last tumor cell. In essence this creates an ongoing battle between the tumor cells and the immune system and it is essential that the immune system win for the host to survive. Learning how to tip the balance in favor of effector T cell survival will be an important strategy for enhancing immunity in cancer- bearing individuals. A recent clinical trial dramatically increased the survival of adoptively transferred tumor Ag-specific T cells in cancer patients and this increase in T cell survival correlated with increased clinical responses. Thus, understanding the mechanisms involved in the T cell survival pathway is crucial to developing new strategies aimed at potentiating tumor immunity in cancer patients. Our group has been studying the biologic function of the TNF-receptor family member, OX40, which has been shown by our group and others to enhance CD4 and CDS T cell survival leading to increased memory. In particular, we have shown that OX40 engagement in tumor-bearing hosts enhances anti-tumor immunity leading to destruction of tumors. We have found that mice cured of tumors through OX40 engagement have tumor-specific memory T cells capable of eliciting potent anti-tumor immunity upon adoptive transfer into naive mice. Therefore we propose to study the mechanism(s) involved with anti-OX40 mediated T cell survival in tumor-bearing hosts to further understand the link between increased tumor Ag-specific T cell survival and immune-mediated therapeutic efficacy.
The specific aims of the grant application are as follows: 1) To understand the contribution that IL-12 makes to anti-OX40 enhanced tumor-specific T cell memory, 2) To elucidate the molecular basis for anti-OX40 enhancement of CD4 and CDS T cell survival, and 3) To determine clinically relevant ways to elicit synergy between anti-OX40 and innate cytokines to enhance tumor-specific T cell memory and destruction of tumors. The knowledge gained from this grant will help us design more effective ways to enhance tumor immunotherapy, and ultimately gain a greater understanding of anti-OX40-specific therapy. OX40-specific augmentation of the immune system has recently increased in relevance, because we have produced clinical grade anti-OX40 antibody and treated the first three cancer patients with this antibody as part of a phase I clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122701-05
Application #
8020895
Study Section
Special Emphasis Panel (ZRG1-CII-M (01))
Program Officer
Mccarthy, Susan A
Project Start
2007-04-01
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$262,259
Indirect Cost
Name
Providence Portland Medical Center
Department
Type
DUNS #
099142093
City
Portland
State
OR
Country
United States
Zip Code
97213
Moran, Amy E; Kovacsovics-Bankowski, Magdalena; Weinberg, Andrew D (2013) The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol 25:230-7
Gough, Michael J; Killeen, N; Weinberg, Andrew D (2012) Targeting macrophages in the tumour environment to enhance the efficacy of ýýOX40 therapy. Immunology 136:437-47
Vasilevsky, Nicole A; Ruby, Carl E; Hurlin, Peter J et al. (2011) OX40 engagement stabilizes Mxd4 and Mnt protein levels in antigen-stimulated T cells leading to an increase in cell survival. Eur J Immunol 41:1024-34
Karulf, Matthew; Kelly, Ann; Weinberg, Andrew D et al. (2010) OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis. J Immunol 185:4856-62
Jensen, Shawn M; Maston, Levi D; Gough, Michael J et al. (2010) Signaling through OX40 enhances antitumor immunity. Semin Oncol 37:524-32
Zhang, Zili; Zhong, Wenwei; Hinrichs, David et al. (2010) Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis. Am J Pathol 177:2912-20
Gough, Michael J; Crittenden, Marka R; Sarff, MaryClare et al. (2010) Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice. J Immunother 33:798-809
Petrausch, Ulf; Poehlein, Christian H; Jensen, Shawn M et al. (2009) Cancer immunotherapy: the role regulatory T cells play and what can be done to overcome their inhibitory effects. Curr Mol Med 9:673-82
Redmond, William L; Gough, Michael J; Charbonneau, Bridget et al. (2007) Defects in the acquisition of CD8 T cell effector function after priming with tumor or soluble antigen can be overcome by the addition of an OX40 agonist. J Immunol 179:7244-53