Immune modulating reagents that trigger the T cell costimulatory molecules GITR and OX40 are being evaluated as anti-cancer agents in early-stage clinical trials. However, 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 GITR and OX40 engagement, novel agonistic reagents directed against murine GITR and OX40 (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 doses. Despite diminished frequencies of CD4+Foxp3+ regulatory T cells (Treg) in the tumor microenvironment (TME) 3 days post-treatment, the presence of myeloid-derived suppressor cells (MDSC) and inhibitory cytokines such as IL-10 and TGFβ appears unaltered and effector T cell production of the Type-1 cytokine IFNγ remains low. Treatment with either GITR or OX40 agonists, however, induces a coordinate increase in CCR7+ dendritic cells in the tumor-draining lymph nodes (TDLN), followed approximately 7 days after treatment by profound expansion of effector T cells expressing the Type-1 chemokine receptor CXCR3. By day 10 post-treatment, particularly with the OX40 agonist, T cells displaying a recently-activated effector phenotype accumulate in the tumor microenvironment and secrete high levels of IFNγ. Collectively, these data suggests a model in which the first level effect of costimulatory treatment is to direct CCR7+ dendritic cells from the TME to the draining lymph nodes. A secondary, systemic response reflects the expansion of highly-reactive CXCR3+ Type-1 T cells in the TDLN and their subsequent trafficking into the TME. The therapeutic efficacy demonstrated in this model by OX40L-Fc, and to a lesser extent GITRL-Fc, strongly supports the translation of such modalities into human clinical trials, while the mechanistic insight gained from these studies suggests that successful immunotherapies will license both local, and perhaps more importantly, systemic Type-1 T cell immunity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2938.