Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies

Abstract

4-1BB (CD137, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Agonistic monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. Preclinical results in a variety of induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies can lead to tumor clearance and durable antitumor immunity. Clinical trials of 2 agonist antibodies, urelumab and utomilumab, are ongoing. Despite initial signs of efficacy, clinical development of urelumab has been hampered by inflammatory liver toxicity at doses >1 mg/kg. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist relative to urelumab. Both antibodies have demonstrated promising results in patients with lymphoma and are being tested in combination therapy trials with other immunomodulatory agents. In an effort to optimally leverage 4-1BB-mediated immune activation, the next generation of 4-1BB targeting strategies attempts to decouple the observed antitumor efficacy from the on-target liver toxicity. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. 4-1BB is a compelling target for cancer immunotherapy and future agents show great promise for achieving potent immune activation while avoiding limiting immune-related adverse events.

Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression

“…S2F), which suggested that despite similar levels of activation, 4–1BB protein expression differed based on genotype. Since 4–1BB is currently tested as a co-stimulatory cancer immunotherapy target (Chester et al, 2018), our description of genotype-dependent effects on expression of 4–1BB in T cells may aid in the development of genetic biomarkers that stratify potential responders to 4–1BB targeted therapies.…”

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

“…3,4 Costimulatory receptors of the Ig superfamily tend to activate phosphatidylinositol 3-kinase (PI3K) leading to protein kinase B (Akt) and downstream nuclear factor jB (NF-jB) activation, while TNFR superfamily members preferentially recruit and activate TNF receptorassociated factors (TRAFs) to potentiate NF-jB activation. 3,6 However, activation of costimulatory receptors can lead to unbridled inflammatory responses with life-threatening consequences. The degree of costimulation received by a T cell is modulated by T cell surface expression of costimulatory molecules, expression of their ligands on APCs and T cell expression of co-inhibitory receptors, many of which compete with costimulatory receptors for the same ligands.…”

“…The CAR T cells lacking a CD28 costimulatory domain showed limited expansion and poor persistence, whereas the T cells expressing a CAR incorporating the CD28 domain underwent a greater degree of expansion and persisted for longer in all six patients. 6 A TNFR superfamily member, 4-1BB, is expressed on a subset of resting CD8 + T cells and is upregulated on both CD4 + and CD8 + T cells following activation. 11,29,30 4-1BB (CD137) 4-1BB (TNFRSF9, CD137) is an activation-induced T cell costimulatory molecule, first described in 1989.…”

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

“…CD137, a representative costimulatory molecule belong to TNF‐receptor superfamily, is an important target for tumor immunotherapy . Its gene expression is inducible in activated T cells .…”