A small molecule TGF-b signaling inhibitor synergizes with agonistic OX40 antibody to elicit a potent anti-tumor and anti-metastatic response in a breast cancer model (66.22)

Abstract SM16 is an orally available small molecule TGF-b signaling inhibitor that binds to the ATP pocket of TGF-b receptor Type 1 and prevents phosphorylation by TGF-BRII following engagement of the ligand. OX40 (CD134) is a member of the TNF-a receptor superfamily and is upregulated on activated CD4 and CD8 T cells. OX40 ligation by its cognate ligand (OX40L) or agonistic antibody (anti-OX40) enhances effector function, expansion and survival of activated T cells. In this study, we examined the therapeutic efficacy and anti-tumor immune response induced by the combination of SM16 plus anti-OX40 in a poorly immunogenic and highly metastatic 4T1 mammary tumor model. Our data show that SM16 synergizes with OX40 to elicit a potent anti-tumor effect against established primary tumors, with a 73% reduction in tumor size and a 92% reduction in the number of metastatic lung nodules; overall 71% of treated mice were either tumor free or showed stable disease by the end of the study. This positive treatment outcome is associated with a two-fold expansion of tumor-infiltrating effector CD8+ T cells and an accumulation of CD4+ and CD8+ cells overall, as well as a high tumor-specific IFN-g response. Depletion of both CD4+ and CD8+ T cells completely abrogates the effect of this therapy, indicating it is T cell dependent. Taken together, these data suggest that combining a TGF-b signaling inhibitor with anti-OX40 is a viable approach for treating metastatic breast cancer.