Tumor necrosis factor receptor superfamily member 9 (4-1BB) costimulatory domain (4-1BB)

The 4-1BB costimulatory domain, derived from Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9), is a pivotal intracellular signaling component used in second and third-generation Chimeric Antigen Receptors (CARs) (UniProt: Q07011). Within a CAR construct, it provides the costimulatory signal necessary for robust T-cell activation and survival following the recognition of a target antigen (PubMed: 30245144). Compared to other costimulatory domains like CD28, the 4-1BB domain is characterized by its ability to promote long-term T-cell persistence and the development of a memory-like phenotype (PubMed: 28939512). It achieves this by shifting T-cell metabolism toward oxidative phosphorylation and fatty acid oxidation, which reduces T-cell exhaustion and enhances sustained anti-tumor activity (PubMed: 27043284). This domain is a core feature of several FDA-approved therapies, including Tisagenlecleucel and Lisocabtagene maraleucel, which are used to treat various B-cell malignancies and multiple myeloma (FDA: Kymriah, Breyanzi). While highly effective, the signaling induced by 4-1BB can lead to significant side effects such as cytokine release syndrome (CRS) and neurotoxicity, which are managed through specific clinical protocols (PubMed: 29937172).

Other names

CD137TNFRSF9Induced by lymphocyte activationILACDw137T-cell antigen 4-1BB

Recruitment of TNFR-associated factors (TRAFs), specifically TRAF1, TRAF2, and TRAF3, to initiate NF-κB, c-Jun N-terminal kinase (JNK), and p38 MAPK signaling pathways, which enhances T-cell survival, metabolic fitness, and long-term memory formation.