Glioblastoma (GBM) is a common and aggressive brain tumour, which is resistant to standard therapies. Clinical and experimental data demonstrated upregulation of Arginase 1 (ARG1) gene and protein in malignant gliomas, particularly in tumour infiltrating microglia and macrophages. Elevated Arginase 1 expression leads to depletion of L-arginine required for T cell and natural killer cell proliferation. A novel, selective small molecule arginase inhibitor - OAT-1746- was developed by OncoArendi Therapeutic SA and we evaluated its antitumour efficacy as a monotherapy and in combination with antibody against PD-1.
Efficacy of the inhibitor in blocking microglia dependent glioma invasion has been determined in Matrigel invasion assays. Its potential cytotoxicity towards microglia and glioma cells in vitro has been evaluated with a MTT metabolism test. Antitumour activity of targeting drugs was assessed in a murine Gl261 glioma model. Tumour volume was measured using an in-vivo imaging system after 21 and 28 days. Immune heterogeneity of glioma microenvironment was analysed by flow cytometry.
The co-culture of microglial cells with glioma cells increased the invasiveness of U87 MG and LN18 glioma cells. This microglia dependent invasion was reduced significantly and in a dose dependent manner in the presence of inhibitor. OAT-1746 orally administrated (twice a day) to animals implanted intracranially with GL-261 glioma cells reduced tumour volumes at day 21st and 28th as determined using an in vivo-imaging X-treme. While tumour growth was reduced with OAT-1746 or anti-PD-1 as monotherapies, the inhibition was higher when combination of OAT-1746 or anti-PD-1 was provided. OAT-1746 effectively crossed the BBB and increased arginine levels in brains of mice bearing gliomas. arginine levels in brains of mice bearing gliomas.
These results demonstrate that arginase is a key mediator of immuno suppression in gliomas, and inhibiting Arg1 shifts the immune response toward a pro-inflammatory environment. Our results suggest that combining OAT-1746 with other immunotherapies may improve responses in glioblastoma.
Molecular Neurobiology, Nencki Institute of Experimental Biology.
Project DIMUNO: “Development of new cancer therapies based on selective antitumour immunomodulators”, co-financed by the National Centre for Research and Development.
All authors have declared no conflicts of interest.