title: 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.
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford University, 269 Campus Drive, CCSR 1140, Stanford, CA, 94305-5151, USA. cchester@stanford.edu.|Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, 94305, USA. cchester@stanford.edu.
authors.forename: Cariad
authors.initials: C
authors.lastname: Chester
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford University, 269 Campus Drive, CCSR 1140, Stanford, CA, 94305-5151, USA.
authors.forename: Siddhant
authors.initials: S
authors.lastname: Ambulkar
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford University, 269 Campus Drive, CCSR 1140, Stanford, CA, 94305-5151, USA.
authors.forename: Holbrook E
authors.initials: HE
authors.lastname: Kohrt
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
keywords: 4-1BB; Antibody-dependent cell-mediated cytotoxicity; CIMT 2015; Checkpoint inhibitors; Combination therapy; Immunotherapy