Cancer-reactive immunity can be identified in tumor-bearing hosts;however, the paucity of immunologic "danger" signals as well as the presence of immunosuppressive factors/cells within the tumor microenvironment appears to tip the balance in favor of tumor progression. We and others have recently found that the addition of immune activating Ab(s) (e.g. anti-OX40, -CD40, -4-1BB, and -CTLA-4) that stimulate both adaptive and innate immunity can tip the balance in favor of tumor immunity and lead to tumor regression. In particular, our group has focused on the immune stimulating properties of agents targeting the OX40 protein in tumor-bearing hosts, which have shown therapeutic promise in several preclinical mouse cancer models. This application focuses on the changes within T cells and macrophages isolated from the tumor microenvironment (TME) that occur following treatment of tumor-bearing mice with OX40 agonists. We hypothesize that immune-specific changes occur within the TME after OX40 agonist administration that reduce local immune suppression leading to T cell-mediated destruction of tumor cells.
The specific aims are as follows;1) To examine the quantitative and qualitative changes in tumor-reactive CD8 T cells within the tumor microenvironment after OX40 agonist treatment, 2) To understand the role that tumor-associated macrophages (TAMs) play in immune suppression of the TME and how OX40 therapy alleviates this suppression and 3) To test whether reshaping the cytokine milieu in the context of OX40 stimulation can create an immune permissive environment within the tumor. OX40-specific augmentation of the immune system has recently increased in relevance, because we have produced clinical grade anti-OX40 and have treated 20 patients as part the first OX40-specific clinical trial (phase I study). Understanding the changes that occur within the TME following OX40 treatment may ultimately discover new pathways and novel mechanisms, which could be the basis for future clinical trials that combine OX40 therapy with other treatment modalities.

Public Health Relevance

Tumors are known to induce local immune suppression, which ultimately allows the cancer to grow unhindered by immune attack. We have found that an immune-stimulating antibody, anti-OX40, delivered to tumor-bearing hosts increases cancer-specific immunity leading positive therapeutic benefit. This project will dissect the immune-specific changes that occur within the tumor microenvironment following anti-OX40 treatment and we will use this information to make the therapy better in the future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102577-10
Application #
8465111
Study Section
Special Emphasis Panel (ZRG1-ONC-H (03))
Program Officer
Welch, Anthony R
Project Start
2003-07-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$287,887
Indirect Cost
$89,754
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
Garrison, Kendra; Hahn, Tobias; Lee, Wen-Cherng et al. (2012) The small molecule TGF-? signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis. Cancer Immunol Immunother 61:511-21
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
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
Jensen, Shawn M; Maston, Levi D; Gough, Michael J et al. (2010) Signaling through OX40 enhances antitumor immunity. Semin Oncol 37:524-32
Redmond, William L; Gough, Michael J; Weinberg, Andrew D (2009) Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo. Eur J Immunol 39:2184-94
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
Gough, Michael J; Ruby, Carl E; Redmond, William L et al. (2008) OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res 68:5206-15
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
Ruby, Carl E; Redmond, William L; Haley, Daniel et al. (2007) Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur J Immunol 37:157-66

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