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Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity¹

Andrew D. Weinberg^2,*, Martin-Muy Rivera^*, Rodney Prell^*, Arden Morris, Trygg Ramstad^*, John T. Vetto, Walter J. Urba^*, Gregory Alvord^§, Campbell Bunce and John Shields

^* Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213; Department of Surgery, Section of Surgical Oncology, Oregon Health Science University, Portland, OR 97201; Cantab Pharmaceuticals, Cambridge, United Kingdom; and ^§ Computer and Statistical Services, National Cancer Institute-Frederick Research and Development Center, Frederick, MD 21702

The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4⁺ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R⁺ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R⁺ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20–55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host’s tumor-specific CD4⁺ T cells. The identification of OX-40R⁺ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.