New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis

Abstract

<jats:p>CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Perturbation of CD137 by CD137L or agonist monoclonal antibodies on activated CD8 T cells protects such antigen-specific cytotoxic T lymphocytes from apoptosis, enhances effector functionalities and favours persistence and memory differentiation. As a consequence, agonist antibodies exert potent antitumour effects in mouse models and the CD137 signalling domain is critical in chimeric antigen receptors (CAR) of CAR T cells approved to be used in the clinic. New formats of CD137 agonist moieties are being clinically developed, seeking potent costimulation targeted to the tumour microenvironment to avoid liver inflammation side effects, that have thus far limited and delayed clinical development.</jats:p>

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

“…4-1BB (CD137, TNFRSF9) is another surface glycoprotein member of the TNF receptor superfamily that is expressed in a variety of immune cells, including T-lymphocytes and NK cells. A-1BB ligation by its natural ligand 4-1BBL (CD137L), expressed by DCs, macrophages and B-cells, among others, induces the activation of NF-kB and MAPK pathways [ 236 ], increasing survival, proliferation and effector function [ 236 , 237 ]. 4-1BB is considered a promising target for immunotherapy in B-NHL patients since microarray analyses have shown the overexpression of 4-1BB in DLBCL and FL biopsies [ 238 ].…”

CD137-stimulated cytotoxic T lymphocytes exert superior tumour control due to an enhanced antimitotic effect on tumour cells

“…One immunomodulator which has received much recent attention is CD137: in 2017 there were 9 trials with therapies targeting CD137; in 2018 there were 36 [2] . Although several anti-CD137 agonists are under clinical evaluation [9] , the mechanisms through which anti-CD137 influences cancer immunotherapy remain under debate [10,11] . CD137 is a costimulatory molecule classified as a member of the Tumour Necrosis Factor Receptor superfamily, which is expressed on both innate and adaptive immune cells.…”

4-1BB (CD137) in anticancer chimeras

“…Although other members of the TNFR family, such as OX40, CD27, or glucocorticoid-induced TNF-related protein, may unleash antitumor immunity (Croft et al, 2013), overall results indicate that 4-1BB is the most potent. Importantly, 4-1BB agonists are synergistic with a variety of cancer immunotherapies, including checkpoint inhibitors (Etxeberria et al, 2020). Agonist anti-CD137 mAbs have been in clinical trials but unfortunately caused Fc receptor (FcR)-dependent immune-mediated liver toxicity (Segal et al, 2017).…”

“…Agonist anti-CD137 mAbs have been in clinical trials but unfortunately caused Fc receptor (FcR)-dependent immune-mediated liver toxicity (Segal et al, 2017). New formats and constructs of CD137 agonists devised to be safer to the liver are back in the clinic (Etxeberria et al, 2020).…”

“…In the recent past, new agonists have been engineered to be given systemically. They are devoid of FcR binding capabilities to avoid liver toxicity but conjugated to antibodies targeting tumor molecules or tumor tissue (Etxeberria et al, 2020), or given as probodies activable by tumor tissue-restricted proteases (unpublished data). Indeed, fibroblast activation protein-targeted 4-1BBL is already in early clinical trials (Claus et al, 2019) as well as anti-PD-L1-CD137 bispecific antibodies (NCT03917381), and more will join this translational adventure soon (Etxeberria et al, 2020).…”