In the last decade, immunotherapies have revolutionised anticancer treatment. However, there is still a number of patients that do not respond or acquire resistance to these treatments. Despite several efforts to combine immunotherapy with other strategies like chemotherapy, or other immunotherapy, there is an â € urgent' need to better understand the immune landscape of the tumour microenvironment. New promising approaches, in addition to blocking co-inhibitory pathways, such those cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 mediated, consist of activating co-stimulatory pathways to enhance antitumour immune responses. Among several new targets, glucocorticoid-induced TNFR-related gene (GITR) activation can promote effector T-cell function and inhibit regulatory T-cell (Treg) function. Preclinical data on GITR-agonist monoclonal antibodies (mAbs) demonstrated antitumour activity in vitro and in vivo enhancing CD8 + and CD4 + effector T-cell activity and depleting tumour-infiltrating Tregs. Phase I clinical trials reported a manageable safety profile of GITR mAbs. However, monotherapy seems not to be effective, whereas responses have been reported in combination therapy, in particular adding PD-1 blockade. Several clinical studies are ongoing and results are awaited to further develop GITR-stimulating treatments.
New emerging targets in cancer immunotherapy: The role of GITR
Buzzatti G.;Dellepiane C.;Del Mastro L.
2020-01-01
Abstract
In the last decade, immunotherapies have revolutionised anticancer treatment. However, there is still a number of patients that do not respond or acquire resistance to these treatments. Despite several efforts to combine immunotherapy with other strategies like chemotherapy, or other immunotherapy, there is an â € urgent' need to better understand the immune landscape of the tumour microenvironment. New promising approaches, in addition to blocking co-inhibitory pathways, such those cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 mediated, consist of activating co-stimulatory pathways to enhance antitumour immune responses. Among several new targets, glucocorticoid-induced TNFR-related gene (GITR) activation can promote effector T-cell function and inhibit regulatory T-cell (Treg) function. Preclinical data on GITR-agonist monoclonal antibodies (mAbs) demonstrated antitumour activity in vitro and in vivo enhancing CD8 + and CD4 + effector T-cell activity and depleting tumour-infiltrating Tregs. Phase I clinical trials reported a manageable safety profile of GITR mAbs. However, monotherapy seems not to be effective, whereas responses have been reported in combination therapy, in particular adding PD-1 blockade. Several clinical studies are ongoing and results are awaited to further develop GITR-stimulating treatments.
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