Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives

Abstract

The tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) are important regulators of the immune system, mediating proliferation, survival, differentiation, and function of immune cells. As a result, their targeting for immunotherapy is attractive, although to date, under-exploited. In this review we discuss the importance of co-stimulatory members of the TNFRSF in optimal immune response generation, the rationale behind targeting these receptors for immunotherapy, the success of targeting them in pre-clinical studies and the challenges in translating this success into the clinic. The efficacy and limitations of the currently available agents are discussed alongside the development of next generation immunostimulatory agents designed to overcome current issues, and capitalize on this receptor class to deliver potent, durable and safe drugs for patients.

Keywords: TNFR; agonism; cancer; co-stimulation; immunotherapy.

Figure 1

Classification of TNFRSF. The TNFRSF can be classified into three sub-families. All twenty-nine members of the family, grouped into three sub-families, are indicated with the number of CRDs on their extracellular region and TNFRSF number in brackets. CRD domains are defined by Uniprot with the exception of RELT which was published as having two CRDs (4). * indicates the receptors with a truncated CRD domain.

Figure 2

Modalities for targeting and activating TNFR. TNFR cross-linking achieved by different mechanisms. (A) Engagement with FcγR enables bivalent mAb cross-linking leading to target receptor clustering. (B) A recombinant hexameric single chain ligand inducing receptor clustering. The hexameric ligand structure is composed of a full Fc domain and six TNFSF ligand ECDs. (C) An antibody shaped bispecific molecule with one antigen binding arm targeting a TNFR e.g. 4-1BB and the other arm targeting a receptor e.g. FAP in the tumor microenvironment. (D) A bispecific molecule in a tetravalent format with two antigen binding arms targeting one receptor e.g. PD-L1 and the other two antigen binding arms in the opposite end of the molecule binding the TNFR e.g. 4-1BB, to induce receptor clustering. The 4-1BB binding domains inserted into the CH3 domain are indicated as a different color in the CH3 domain. TNFR; tumor necrosis factor receptor, FcγR; Fc gamma receptor, 4-1BBL; 4-1BB ligand, FAP; fibroblast activation protein, PD-L1; programmed death ligand 1.