4-1BB: A promising target for cancer immunotherapy

Abstract

Immunotherapy, powered by its relative efficacy and safety, has become a prominent therapeutic strategy utilized in the treatment of a wide range of diseases, including cancer. Within this class of therapeutics, there is a variety of drug types such as immune checkpoint blockade therapies, vaccines, and T cell transfer therapies that serve the purpose of harnessing the body’s immune system to combat disease. Of these different types, immune checkpoint blockades that target coinhibitory receptors, which dampen the body’s immune response, have been widely studied and established in clinic. In contrast, however, there remains room for the development and improvement of therapeutics that target costimulatory receptors and enhance the immune response against tumors, one of which being the 4-1BB (CD137/ILA/TNFRSF9) receptor. 4-1BB has been garnering attention as a promising therapeutic target in the setting of cancer, amongst other diseases, due to its broad expression profile and ability to stimulate various signaling pathways involved in the generation of a potent immune response. Since its discovery and demonstration of potential as a clinical target, major progress has been made in the knowledge of 4-1BB and the development of clinical therapeutics that target it. Thus, we seek to summarize and provide a comprehensive update and outlook on those advancements in the context of cancer and immunotherapy.

High 4-1BB Expression in PBMCs and Tumor Infiltrating Lymphocytes (TILs) in Patients with Head and Neck Squamous Cell Carcinoma

“…Few studies have examined the amounts of the protein 4-1BB in various cancer cells such as lung, pancreas, etc. [11][12][13] Our study found increased expression of 4-1BB in PBMCs from OC and OPC compared to HC (►Fig. 1A).…”

“…Consequently, combining multiple medications, such as PD-1 with 4-1BB, or Programmed death-ligand 1 (PD-L1) with 4-1BB, to improve the safety and efficacy of cancer therapies is an alternative novel cancer immunotherapy strategy. 4,13,29…”

What is the optimal duration, dose and frequency for anti-PD1 therapy of non-small cell lung cancer?

“…63 Agonistic antibodies targeting co-stimulatory receptors such as 4-1BB may again yield different results. 64 Notably, unlike anti-PD1-directed agents, the 4-1BB agonist urelumab was found to have dose-limiting toxicities. 65 In contrast, the 4-1BB agonistic antibody utomilumab was found not to have dose-limiting toxicities in the range tested.…”

The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress

“…Meant to act as guards against excessive immune response, they can also act as avenues for tumor cells to escape immunosurveillance. , A few well-known examples of inhibitory immune checkpoint molecules include programmed cell death protein-1 (PD-1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; also known as B7, CD152), B and T lymphocyte attenuator (BTLA; also known as CD272), and lymphocyte-activation gene 3 (LAG-3; also known as CD223) , among others. For the stimulatory pathways, glycoproteins such as OX40 receptors (also known as CD134 and TNFRSF4) , and 4–1BB (also known as CD137) are few well-known examples of immune checkpoint molecules. Expressed on cell surface, immune checkpoint molecules modulate the activity of T cells and it is this feature that can be exploited to our advantage.…”