Modulation of GITR for cancer immunotherapy

Abstract

Modulation of co-inhibitory and co-stimulatory receptors of the immune system has become a promising new approach for immunotherapy of cancer. With the recent FDA approval of CTLA-4 blockade serving as an important proof of principal, many new targets are now being translated into the clinic. Preclinical research has demonstrated that targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR), a member of TNF receptor superfamily, by agonist antibodies or natural ligand, can serve as an effective anti-tumor therapy. In this review, we will cover this research and the rationale that has led to initiation of two phase 1 clinical trials targeting GITR as a new immunotherapeutic approach for cancer.

Figure 1

Model of GITR function during an immune response. During the initial phase of priming, naïve T cells are activated by interactions between the TCR and MHC molecules, receiving co-stimulation through CD28 binding to either CD80 or CD86. After passing this checkpoint, activated T cells enter secondary rounds of priming and expansion, upregulating GITR 24–72 h after this initial activation. If GITR-L is expressed by DCs, it alters both the quality and the quantity of the ensuing immune response. The net result of which is enhanced inflammatory response, with increased persistence of the antigen-specific T cells.

Figure 2

Modulating GITR to enhance immunotherapy. Under steady-state conditions, this immune response is insufficient to mediate tumor regression. Teff generated are unable to overcome an inhibitory tumor environment and remain vulnerable to regulatory T cell (Treg)-mediated suppression. Provision of additional GITR stimulus during the secondary stages of priming and expansion, through agonist anti-GITR antibody, soluble GITR ligand or DC vaccines expressing soluble GITR modulates the outcome of both Teff and Treg tumor responses. Teffs demonstrate greater proliferation, effector function, and resistance to suppression, while Tregs show decreased tumor infiltration and stability, with loss of foxp3 expression. This results in augmented intra-tumor Teff:Treg ratio which favors tumor immunity and regression.