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

Abstract

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.

Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer

“…Agonists that activate T cells via costimulatory molecules could be combined with BCG; one such molecules is OX40, a cell surface molecule which serves as a potent costimulatory signal to effector T cells, and is in phase I trials in patients with advanced cancer (NCT02219724) (32, 33). Similarly, 4-1BB is another costimulatory molecule expressed on activated T cells being studied in human cancer trials (NCT02111863), which—leads to increased proliferation of anti-apoptotic molecules on lymphocytes (34). Another approach would be to combine BCG with a TLR agonist, transmembrane receptors expressed on immune cells that have been shown to be present in NMIBC (35).…”

Delivering safer immunotherapies for cancer

“…Urelumab was first tested in melanoma, non-small cell lung cancer, and other advanced solid tumors [99]. During dose escalation of urelumab, dose limiting grades 3 and 4 neutropenia were accompanied by frequent yet mild adverse outcomes including leukopenia, thrombocytopenia, and hyperbilirubinemia, mirroring toxicology results in mice.…”

Chimeric Antigen Receptor T-cell Therapy for Cancer: A Basic Research-Oriented Perspective

“…CD28 is a well-characterized costimulatory molecule in T-cell priming that leads to signaling cascades by augmenting TCRζ signaling, and permits enhanced survival and memory formation [43]. The other costimulatory molecule, 4-1BB, is expressed on the surface of activated T cells, and is known for its role in memory formation and T-cell maintenance [44,45]. Incorporating CD28 or 4-1BB into the CAR cytoplasmic domain prolonged CAR T-cell survival and improved in vivo antitumor efficacy in preclinical models [42,46,47].…”