4-1BB agonism: adding the accelerator to cancer immunotherapy

The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8(+) T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously “removing the brakes” via blocking inhibitory signaling and “stepping on the accelerator” via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.