Our group has focused on using agonists to the TNF-receptor, OX40, to enhance anti-tumor immunity/activity. OX40 agonists have T cell costimulatory activity and are known to increase CD4 and CD8 T cell proliferation, effector function, and memory T cell survival. Injecting OX40 agonists into cancer-bearing hosts leads to increased anti-tumor immunity, which has been observed in several different mouse tumor models. The OX40 agonist anti-tumor activity is dependent on both CD4 and CD8 T cells and mice cured via OX40 agonists are immune to tumor rechallenge, suggesting an enhanced tumor-specific memory T cell response. The preclinical data led to the development of a mouse anti-human OX40 agonist Ab that was recently tested in a phase I clinical trial. The phase I trial treated metastatic cancer patients from several different tumor types, which included melanoma, renal cell carcinoma, ovarian cancer, lung cancer, colon cancer, and prostate cancer. A dose escalation of the human OX40 Ab was well-tolerated and showed increased signs of T cell proliferation in both CD4/FoxP3neg and CD8 T cells (via Ki-67 staining) that peaked at the 0.4 mg/kg dose level. We also found that OX40-induced proliferating CD8 T cells showed increased levels of immune activation, as these cells had increased levels of CD38 and HLA-DR on their surface. One round of treatment led to regression of at least one metastatic lesion in 12/30 patients treated, however there were no partial or complete responses by RECIST criteria. In a select group of patients we were able to assess anti-tumor immune responses pre- and post-anti-OX40 treatment. We found in 3 of 4 patients that the anti-tumor immune responses were increased following anti-OX40 administration. In summary, OX40 agonist stimulation enhances anti-tumor immunity in cancer-bearing hosts and this activity was translated to late stage cancer patients. The human OX40 agonist used in these clinical studies was a mouse Ab. Hence it could only be administered once and had a relatively short half-life in vivo, therefore humanized versions of the OX40 agonists will be tested in future clinical trials.
Citation Format: Andrew D. Weinberg. Translation of an OX40 agonist: Putting a foot on an immunologic gas pedal. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA12.