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

Abstract

Twenty-five years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitumor 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 inflammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and efficacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecific 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 developed in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profiles.

Tregs constrain CD8+T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

“…Signaling through 4-1BB in CD8 + T cells leads to proliferation, enhanced survival, cytokine production, improved memory formation, and altered metabolism (11)(12)(13)(14)(15). Treating mice with agonist ɑ4-1BB antibodies as a monotherapy or in combination therapies is highly efficacious in several preclinical mouse cancer models (16,17). However, toxicity has hampered clinical translation of such antibodies, with lethal liver toxicities reported in early phase 2 trials of Urelumab, the first ɑ4-1BB agonistic antibody to enter the clinic (18).…”

Time-dependent enhancement of mRNA vaccines by 4-1BB costimulation

“…In this study, we interrogated whether mRNA vaccines could be improved by triggering 4-1BB, a costimulatory molecule involved in T cell activation. 4-1BB costimulatory antibodies have been clinically tested in autoimmunity and cancer immunotherapy 17, 18 , and the signaling molecules involved in 4-1BB costimulation are included in chimeric antigen receptor (CAR) T cell therapies 29 . Although 4-1BB costimulation is known to play an important role in immune activation, it could also cause immunosuppression in certain contexts, and it is unclear how the timing of 4-1BB costimulation determines these opposite outcomes.…”

PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer

“…The use of the CD137 agonist could further promote CD8 + T-cell expansion and activation and also relieve the immunosuppressive effects from Tregs, resulting in a synergistic antitumor effect. Similar combination strategies with the CD137 agonist to enhance efficacy have received considerable attention since the early discovery of the CD137 agonist ( 31 – 33 ), such as chemotherapy ( 34 , 35 ), radiotherapy ( 36 , 37 ), or cancer vaccines ( 38 , 39 ), possibly through the enhanced immunogenicity with more tumor antigen cross-presentation to improve the efficacy of the immune checkpoint inhibitors ( 40 ).…”