Tags

Type your tag names separated by a space and hit enter

Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies.
Blood. 2018 01 04; 131(1):49-57.Blood

Abstract

4-1BB (CD137, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Agonistic monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. Preclinical results in a variety of induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies can lead to tumor clearance and durable antitumor immunity. Clinical trials of 2 agonist antibodies, urelumab and utomilumab, are ongoing. Despite initial signs of efficacy, clinical development of urelumab has been hampered by inflammatory liver toxicity at doses >1 mg/kg. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist relative to urelumab. Both antibodies have demonstrated promising results in patients with lymphoma and are being tested in combination therapy trials with other immunomodulatory agents. In an effort to optimally leverage 4-1BB-mediated immune activation, the next generation of 4-1BB targeting strategies attempts to decouple the observed antitumor efficacy from the on-target liver toxicity. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. 4-1BB is a compelling target for cancer immunotherapy and future agents show great promise for achieving potent immune activation while avoiding limiting immune-related adverse events.

Authors+Show Affiliations

Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA.Department of Immunobiology, Yale University School of Medicine, New Haven, CT.Department of Immunobiology, Yale University School of Medicine, New Haven, CT.Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain; and. Centro de Investigacion Biomedica en Red, Madrid, Spain.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

29118009

Citation

Chester, Cariad, et al. "Immunotherapy Targeting 4-1BB: Mechanistic Rationale, Clinical Results, and Future Strategies." Blood, vol. 131, no. 1, 2018, pp. 49-57.
Chester C, Sanmamed MF, Wang J, et al. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood. 2018;131(1):49-57.
Chester, C., Sanmamed, M. F., Wang, J., & Melero, I. (2018). Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood, 131(1), 49-57. https://doi.org/10.1182/blood-2017-06-741041
Chester C, et al. Immunotherapy Targeting 4-1BB: Mechanistic Rationale, Clinical Results, and Future Strategies. Blood. 2018 01 4;131(1):49-57. PubMed PMID: 29118009.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. AU - Chester,Cariad, AU - Sanmamed,Miguel F, AU - Wang,Jun, AU - Melero,Ignacio, Y1 - 2017/11/08/ PY - 2017/06/13/received PY - 2017/09/06/accepted PY - 2017/11/10/pubmed PY - 2018/10/13/medline PY - 2017/11/10/entrez SP - 49 EP - 57 JF - Blood JO - Blood VL - 131 IS - 1 N2 - 4-1BB (CD137, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Agonistic monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. Preclinical results in a variety of induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies can lead to tumor clearance and durable antitumor immunity. Clinical trials of 2 agonist antibodies, urelumab and utomilumab, are ongoing. Despite initial signs of efficacy, clinical development of urelumab has been hampered by inflammatory liver toxicity at doses >1 mg/kg. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist relative to urelumab. Both antibodies have demonstrated promising results in patients with lymphoma and are being tested in combination therapy trials with other immunomodulatory agents. In an effort to optimally leverage 4-1BB-mediated immune activation, the next generation of 4-1BB targeting strategies attempts to decouple the observed antitumor efficacy from the on-target liver toxicity. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. 4-1BB is a compelling target for cancer immunotherapy and future agents show great promise for achieving potent immune activation while avoiding limiting immune-related adverse events. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/29118009/Immunotherapy_targeting_4_1BB:_mechanistic_rationale_clinical_results_and_future_strategies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)32584-2 DB - PRIME DP - Unbound Medicine ER -