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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ONC-H (03))
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Welch, Anthony R
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Providence Portland Medical Center
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Duhen, Thomas; Duhen, Rebekka; Montler, Ryan et al. (2018) Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun 9:2724
Moran, Amy E; Polesso, Fanny; Weinberg, Andrew D (2016) Immunotherapy Expands and Maintains the Function of High-Affinity Tumor-Infiltrating CD8 T Cells In Situ. J Immunol 197:2509-21
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
Redmond, William L; Triplett, Todd; Floyd, Kevin et al. (2012) Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression. PLoS One 7:e34467
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
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Weinberg, Andrew D; Morris, Nicholas P; Kovacsovics-Bankowski, Magdalena et al. (2011) Science gone translational: the OX40 agonist story. Immunol Rev 244:218-31
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

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