CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary

Twenty-fi ve years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitu-mor immunity. Mouse models indicated that anti-CD137 agonist antibodies synergized with various other therapies. In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver infl ammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and effi cacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecifi c constructs, are in early-phase trials and are showing promising safety and clinical activity.Significance: CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in cancer immunotherapy strategies as discovered 25 years ago. Following initial attempts that met unacceptable toxicity, new waves of constructs acting agonistically on CD137 are being devel-oped in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profi les.

Automated summary

Twenty-five years ago, it was discovered that agonist anti-CD137 monoclonal antibodies enhanced CD8+ T-cell antitumor immunity and effectively eradicated transplanted mouse tumors. Despite causing severe liver inflammation in some patients, the agonist antibody urelumab showed evidence of activity against melanoma and non-Hodgkin lymphoma. CD137's signaling domain has been incorporated into chimeric antigen receptors, improving their efficacy. New CD137 agonists, primarily based on bispecific constructs, are currently being tested in early-phase trials and are showing promising safety and clinical activity.