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

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• CD137 (4-1BB) is a costimulatory receptor on T and NK lymphocytes, crucial for immune responses.
• Exploiting CD137 agonism represents a significant strategy in cancer immunotherapy.
• Early anti-CD137 antibodies demonstrated efficacy but faced toxicity challenges.

Purpose of the Study:

• To review the evolution of CD137 agonist antibodies in cancer immunotherapy.
• To highlight advancements in CD137-targeted therapies and their clinical implications.
• To discuss the safety and efficacy profiles of novel CD137 agonist constructs.

Main Methods:

• Review of preclinical studies on anti-CD137 monoclonal antibodies in mouse tumor models.
• Analysis of clinical trial data for urelumab, an agonist anti-CD137 antibody.
• Examination of emerging bispecific CD137 agonists in early-phase clinical trials.

Main Results:

• Anti-CD137 antibodies eradicated tumors in mouse models via enhanced CD8+ T-cell immunity.
• Urelumab showed single-agent activity in melanoma and non-Hodgkin lymphoma but caused liver inflammation.
• Newer bispecific CD137 agonists exhibit promising safety and clinical activity.

Conclusions:

• CD137 agonism is a validated approach for cancer immunotherapy.
• Advancements in construct design have improved the safety and efficacy of CD137 agonists.
• Novel CD137-based therapies hold significant promise for cancer treatment.