MEDI1873, a GITR ligand fusion protein (GITRL FP), induces effector T-cell proliferation, modulates T-regulatory cell function and has the potential to combine with checkpoint inhibitors

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is part of a system of signals involved in controlling T-cell activation. MEDI1873 is a novel hexameric human GITR agonist comprising an IgG1 Fc domain, a coronin 1A trimerisation domain and the human GITRL extracellular domain (ECD) that is currently being assessed in a Phase 1 clinical study (NCT02583165) in patients with solid tumors. MEDI1873 exhibits in vitro superiority to an anti-GITR antibody with respect to evoking robust GITR agonism, T-cell activation and clustering of Fc gamma receptors. Using in vitro assay systems, MEDI1873 recapitulates aspects of GITR targeting previously described in mice, including modulation of regulatory T-cell (Treg) suppression and the ability to increase the CD8:CD4 T-cell ratio via antibody-dependent T-cell cytotoxicity. Pharmacodynamic assessment of an agonistic mouse GITRL FP (mGITRL FP) in the CT26 model of colorectal cancer demonstrated activation and proliferation of peripheral CD4+ and CD8+ T cells coincident with an increased depletion of intratumoral Tregs, likely through Fc mediated effector functions. Furthermore, CT26 tumor growth studies indicated the mGITRL FP could result in significant antitumor activity. These data provide evidence that MEDI1873 is a novel, potent GITR agonist with the potential to modulate T-cell responses and enhance anti-tumor immunity. Combinations of immunotherapies are generating exciting results in the clinic, therefore, we sought to assess the potential for GITRL FPs to combine with antibodies targeting either anti-PD-L1 (durvalumab) or anti-CTLA-4 (tremelimumab) using both in vitro and in vivo systems. In vitro studies where MEDI1873 was combined with either durvalumab or tremelimumab showed that both combinations have the potential to enhance interleukin-2 release in a superantigen-stimulation of human peripheral blood mononuclear cells (PBMCs) compared to checkpoint blockade alone. Further evidence to support the potential for combinatorial antitumor activity was generated in the CT26 model where either 0.2mg/kg mGITRL combined with 10mg/kg anti-mouse PD-L1 or 0.1mg/kg mGITRL combined with 5mg/kg anti-mouse CTLA-4 antibodies resulted in enhanced antitumor activity versus monotherapies alone. Overall, our data suggest that therapeutically targeting GITR with a multimeric fusion protein, GITRL FP, may provide increased agonistic potential versus an antibody, and have the ability to both activate effector T-cells and modulate Tregs through suppression and/or depletion. Finally, combination studies provide preclinical evidence to support the rationale for combination of MEDI1873 with anti-PD-L1 or anti-CTLA-4 antibodies further reinforcing the potential of targeting the GITR pathway as a therapeutic approach to treating patients with cancer