Engagement of the TNF-R family member OX40 in vivo enhances anti-tumor immunity.

AD Weinberg PhD^a, S Shu PhD^b, W Urba MD PhD^a

^aProvidence Portland Medical Center, Portland, OR, United States, ^bClevelend Clinic, Cleveland, OH, United States

Aim: OX40, a member of the TNF-receptor family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of OX40, with either OX40 ligand (OX40L) or an agonist antibody, delivers a strong proinflammatory costimulatory signal to effector T cells. OX40+ T cells isolated from tumors or tumor infiltrating lymph nodes show specificity for tumor reactivity. We therefore investigated whether engagement of OX40 in vivo during tumor priming would enhance a tumor-specific T cell response. Method: Mice were inoculated s.c. with various tumors from different tissue specificity. On days 3 and 7 after tumor inoculation the tumor bearing mice were injected i.p. with either OX40L:Ig or anti-OX40. The mice were then evaluated for evidence of tumor growth and tumor-free survival for >60 days. Results: Injection of OX40L:Ig or anti-OX40 in vivo 3 days after tumor inoculation resulted in a significant improvement in the percentage of tumor-free survivors (20-60%) in 8 differenct murine tumors derived from 5 separate tissues (melanoma, breast cancer, sarcoma, glioma, and colon cancer). The anti-OX40 effect was dose-dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of OX40 in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host's tumor-specific CD4+ T cells. We have also identified OX40+ T cells clustered around human tumor cells in breast cancer, head and neck cancer, melanoma, bladder cancer, and prostate cancer. Conclusions: Engagement of OX40 in vivo in tumor-bearing mice greatly enhances tumor-free survival in a wide variety of tumor models. This is enhancement is due to increased T cell immunity to tumor Ags. Since OX40+ T cells were identified at the sites of tumor growth, OX40 engagement in patients with a wide variety tumor types may be a practical approach for expanding and enhancing the function of tumor-reactive T cells. The promising preclinical data has led to the production of an anti-human OX40 Ab that will be taken to clinical trials in the coming year. Keywords: tumor-immunotherapy, T cells, costimulation, and OX40

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 995 (Immunotherapy).