4-1BB, also well-known as CD137 and TNFRSF9, is an inducible costimulatory protein from the tumor necrosis factor (TNF) superfamily best known for enhancing CD8+ T cell proliferation and survival in a CD28-independent manner. Its ligand, 4-1BBL (CD137L or TNFSF9), is mainly expressed on myeloid cells. Similar to other members of the TNF superfamily, 4-1BB signaling is bidirectional. Thus, ligation influences the function of ligand-bearing cells and those expressing the receptor. 4-1BB signaling preferentially expands CD8+ T cells and induces Th1 responses. Its reverse signaling, via 4-1BBL, amplifies the innate immune responses by enhancing monocyte proliferation, migration, and maturation into Th1-inducing DCs and augmenting cytokine production by peritoneal macrophages.
Fig.1 Multimerization of 4-1BB by natural ligand and agonist mAbs. (Melero, 2008)
Targeting 4-1BB in Immuno-Oncology
4-1BB and 4-1BBL pathway has been well characterized in the process of hematopoiesis, inflammation, and immune tolerance. The dual ability of 4-1BB to stimulate strong effector T cell responses toward pathogens while restricting autoimmune disease has made this receptor an attractive target for cancer immunotherapy. Although agonist antibodies have been the best-studied modality for activating 4-1BB, the immune pathologies associated with their use have prompted the development of alternate therapeutics. Promising 4-1BB targeted therapies include agonist antibodies, soluble 4-1BBL, and aptamers. Clinical trials of two leading agonist antibodies are ongoing in multiple cancer indications, and both antibodies demonstrate distinct activities in the clinic.
Table 1 Murine antitumor models targeted the 4-1BB and 4-1BBL pathway. (Cheuk, 2004)
Combinational Therapies targeting 4-1BB
The addition of 4-1BB agonists to other therapeutic modalities could potentiate more robust antitumor responses while necessitating reduced dosing, therefore limiting the severity of 4-1BB associated adverse events. So far, many studies have shown cooperative and synergistic therapeutic benefits by combining 4-1BB agonists with different antitumor therapies. The most alluring combinations are those that combine 4-1BB agonists with T cell immune checkpoint blockade.
Combining anti-4-1BB with gene therapy and oncolytic virotherapy
Combining 4-1BB agonists with CTLA-4 blockade
Combining 4-1BB agonists with radiation therapy
Combining 4-1BB activation with chemotherapy
Combining 4-1BB agonists with TNF receptor agonists
Targeting 4-1BB and the PD-1/PD-L1 axis to elicit potent antitumor effects