4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity

Abstract

Immunotherapy is a rapidly expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. Of the many approaches currently under study to boost anti-tumor immune responses; modulation of immune co-receptors on lymphocytes in the tumor microenvironment has thus far proven to be the most effective. Antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) has become the first FDA approved immune checkpoint blockade; however, tumor infiltrating lymphocytes express a diverse array of additional stimulatory and inhibitory co-receptors, which can be targeted to boost tumor immunity. Among these, the co-stimulatory receptor 4-1BB (CD137/TNFSF9) possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-tumor lymphocytes. While functional studies of 4-1BB have focused on its prominent role in augmenting cytotoxic CD8 T cells, 4-1BB can also modulate the activity of CD4 T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells. 4-1BB’s expression on both T cells and antigen presenting cells, coupled with its capacity to promote survival, expansion, and enhanced effector function of activated T cells, has made it an alluring target for tumor immunotherapy. In contrast to immune checkpoint blocking antibodies, 4-1BB agonists can both potentiate anti-tumor and anti-viral immunity, while at the same time ameliorating autoimmune disease. Despite this, 4-1BB agonists can trigger high grade liver inflammation which has slowed their clinical development. In this review, we discuss how the underlying immunobiology of 4-1BB activation suggests the potential for therapeutically synergistic combination strategies in which immune adverse events can be minimized.

PD-1 and PD-L1 blockade in gastrointestinal malignancies

“…The co-stimulatory receptor 4-1BB (CD137/TNFSF9) is expressed on T cells and antigen presenting cells and can promote survival, expansion and enhanced effector function of activated anti-tumour cytotoxic CD8 T cells [57]. It can also modulate activity of CD4 T cells, B cells, natural killer (NK) cells, monocytes, macrophages and dendritic cells [57].…”

NK cells and cancer: you can teach innate cells new tricks

“…CD137 (also known as 4-1BB and TNFRSF9) is expressed on both cytotoxic T cells and activated NK cells, and agonist mono clonal antibodies augment antitumour activity in mouse models 122 , although there are conflicting data on the role of CD137 in NK cell activation 123 . Agonist CD137 antibodies enhance the human NK cell-mediated killing of breast tumours 124 and B cell lymphomas 125 induced by trastuzumab and rituximab, respectively.…”

Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

“…Its ligation with agonist moieties, such as mAbs, its natural ligand 4-1BBL, or RNA aptamers, enhances CTL-mediated antitumor immunity (8)(9)(10) as a result of multiple mechanisms (11,12). Such functions are being exploited in cancer clinical trials with the agonist mAbs urelumab and utomilumab (13)(14)(15).…”