According to the American Cancer Society, over 1.5 million new cancer cases will be diagnosed this year, a figure that is expected to rise with the aging population. Chemotherapy and radiation are the current “gold standards” for cancer treatment, but these therapies are marginally effective, toxic, and serve to diminish the quality of life for cancer patients. Immunotherapy represents an attractive alternative to these traditional treatment regimens. Despite overwhelming evidence that the immune system is capable of recognizing and eliminating tumors, both spontaneously and in response to immune-based therapy, such protection is abrogated in the face of compensatory immunosuppressive events characteristic of progressive disease. Thus, a major goal of novel immune-based therapies is the coordinate silencing of regulatory circuits and amplification of protective T cell function.

While immune modulating reagents that trigger the T cell costimulatory molecules OX40 and GITR are currently being evaluated in early-phase clinical trials, little pre-clinical information is available regarding the efficacy and mechanism(s) of action for these agents in the setting of advanced, well-established disease. To further characterize the molecular, cellular, and treatment-associated consequences of OX40 and GITR engagement, novel agonistic reagents directed against murine OX40 and GITR (ligand-Fc fusion proteins) were recently constructed and characterized in vitro. We now show that the growth of well-established, day 17 sarcomas is significantly inhibited or ablated by a short course of either treatment, with OX40L-Fc demonstrating superior anti-tumor efficacy over GITRL-Fc at comparable dosing. Both treatments were capable of eliminating regulatory T cells within tumors, inducing profound proliferation of T effector cells in the tumor-draining lymph node, and promoting the recruitment of these expanded effector cells to the tumor microenvironment. However, OX40L-Fc therapy mediated additional, T cell-independent effects, including the activation of tumor-localized dendritic and endothelial cell subsets. These changes rendered the tumor microenvironment more immunogenic and permissive to the infiltration of treatment-induced, protective immune cells. The pleiotropic anti-tumor effects demonstrated in this model by OX40L-Fc, and to a lesser extent GITRL-Fc, strongly supports the further translation of such modalities into human clinical trials, either as single agents or in the context of combinational immunotherapy.