TNFR A g onists : A Review of Current Biolo g ics Tar g etin g OX 40 , 4-1 BB , CD 27 , and GITR

Background Immunotherapy is a rapidly evolving field with the goal of using the patients’ immune system to attack cancer. Much attention in the field has been given to inhibitory checkpoints, whereby T cells that have upregulated inhibitory molecules such as CTLA-4, PD-1/PD-L1, TIM-3 (T0cell immunoglobulin mucin-3), and LAG-3 can effectively turn down effector functions such as cytokine release and cytotoxicity—both of which are required to effectively kill tumor cells. This ratcheting down of effector function can be impeded by targeting these inhibitory molecules through the administration of monoclonal antibodies (mAbs) known as checkpoint inhibitors. However, despite the success of checkpoint blockade with biologics such as anti-CTLA-4 (aCTLA-4) and anti-PD-1 (aPD-1) mAbs, a significant proportion of patients that receive these treatments do not develop therapeutic responses, which highlights the need for more effective therapies. Optimal T-cell activation requires 2 events: signal 1, which is recognition of the cognate peptide/major histocompatibility complex (MHC) by a specific T-cell receptor (TCR), and signal 2, which is ligation of the CD28 costimulatory receptor by its ligands B7.1/B7.2 (CD80/CD86). Together, these are commonly known as T-cell priming. However, in addition to the initial priming event, further signaling is necessary to drive T-cell differentiation and potentiate the development of effector and memory cell subsets; these events enable robust tumor killing activity, in vivo. The tumor necrosis factor receptors (TNFRs), including glucocorticoid-induced TNFR (GITR; CD357), CD27, OX40 (CD134), and 4-1BB (CD137), are a family of proteins responsible for transducing these additional costimulatory signals. In order to harness this important signaling cascade, agonist mAbs and specific ligand complexes have been developed that can engage with these TNFRs and activate downstream events. In this review, we will discuss the biology of TNFRs, the current preclinical and clinical trials targeting these receptors, and potential synergy with other therapies in order to enhance anti-tumor immunity.