CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

Abstract

Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8+ T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors.

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

“…In animal models, CD137-activating antibodies showed anti-tumor activity [ 50 ]. Currently, there are a number of early human trials ongoing, especially on combinations with other checkpoint inhibitors in several malignancies, including breast cancer, colon cancer and other advanced malignancies [ 22 , 23 , 50 ]. The data from the current study underline the possible role of CD137L/CD137 signaling in OSCC pathophysiology as well as the potential therapeutic approach.…”

“…BTLA expression indicates terminally exhausted lymphocytes and was shown to be correlated with lung cancer progression [ 21 ]. CD137 is an activating checkpoint receptor of T-cells and NK cells but also of antigen-presenting cells [ 22 ]. The corresponding ligand CD137L is expressed on antigen-presenting cells [ 23 ].…”

“…The corresponding ligand CD137L is expressed on antigen-presenting cells [ 23 ]. There are early ongoing trials with activating CD137 antibodies for cancer immunotherapy [ 22 , 23 ]. Glucocorticoid-induced tumor necrosis factor receptor (GITR) is an activating receptor of T-lymphocytes.…”

Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity

“…Thus, for these molecules, combination therapy with PD-D/PD-L1 inhibitors or other agents, such as CD3 bispecific T cell engagers, could potentially activate signal 1. In addition, a few PD-L1/CD137 bispecific antibodies are currently under clinical development and are similar to IBI319 34 , 35 . PD-L1/CD137 bispecific antibodies may have advantages in tumour targeting due to the broad PD-L1 expression on tumour cells.…”

Combinatorial immunotherapy induces tumor-infiltrating CD8+T cells with distinct functional, migratory, and stem-like properties

“…9 10 In contrast, agonism of OX40 and 4-1BB has also been explored as an attractive antitumor immunotherapeutic strategy due to the capacity of these molecules to elicit more potent T cell responses. [11][12][13] Numerous preclinical studies comparing the efficacy of anti-OX40 and anti-4-1BB agonists alone or combined with an anti-PD-(L)1 antagonist have suggested synergism between the treatment components. [14][15][16][17] This synergism resulted in CD8 + T cell responses of larger magnitude and durability, ultimately translating to an increased survival benefit.…”