Abstract A195: CB-1158 inhibits the immuno-oncology target arginase and causes an immune mediated anti-tumor response

Abstract

Abstract The role of myeloid derived suppressor cells (MDSCs) has become increasingly recognized as an important mechanism of tumor immune evasion. However, to date there are no effective means to antagonize the immunosuppressive activity of these cells in patients. MDSCs suppress cytotoxic T-cells and Natural Killer cells through the secretion of the enzyme arginase which depletes local arginine concentrations. The depletion of arginine in the tumor microenvironment renders cytotoxic T-cells unable to proliferate and therefore unable to effectively mount an anti-tumor attack. Similarly, M2 macrophages and polymorphonuclear cells (PMNs) express high levels of arginase and may contribute to the local suppression of immune responses. Restoration of arginine levels in the tumor microenvironment via arginase inhibition would be expected to allow T-cell activation and proliferation to occur and result in T-cell mediated anti-tumor responses. We have developed novel, potent, and specific inhibitors of arginase. Our clinical candidate CB-1158 has an IC50 of less than 100 nM in a recombinant human arginase assay. As expected, inhibition of arginase in cell culture does not have a direct anti-proliferative effect on any cell type tested. However, in Peripheral Blood Mononuclear Cells (PBMCs) from a patient with renal cell carcinoma containing both suppressive MDSCs and cytotoxic T-cells, the addition of an arginase inhibitor to the MDSC/T-cell co-culture resulted in a dose-dependent increase in T-cell proliferation relative to vehicle controls. CB-1158 has high oral bioavailability in mice and rats. In mice bearing Lewis Lung Carcinoma (LLC) syngeneic tumors, treatment with CB-1158 results in a 3-4 fold increase in tumor arginine levels with a clear pharmacokinetic/pharmacodynamic relationship. The pharmacodynamic effect of arginase inhibition in tumors was sustained throughout a 24-hour period using a twice-daily oral dosing schedule and has been observed in multiple syngeneic models. Moreover, systemic plasma arginine levels are significantly increased in mice following dosing with CB-1158. Importantly, oral dosing with CB-1158 results in single agent anti-tumor efficacy in the LLC model in C57.Bl/6 mice. In contrast, treatment of immunocompromised C57/scid mice bearing LLC tumors with CB-1158 had no effect on tumor growth. This finding is consistent with the observed anti-tumor efficacy in immune competent mice being mediated through an immune mechanism. Evaluation of tumors treated with arginase inhibitors revealed an increase in CD3+ T-cell infiltrates further supporting an immune-based mechanism of action. CB-1158 has been very well tolerated in rodents with no impact on body weights or serum chemistry enzymes following multi-week dosing schedules. CB-1158 is a first-in-class arginase inhibitor that targets the immunosuppressive effects of myeloid cells in the tumor microenvironment and is currently in development as a novel immuno-oncology strategy. Based on this novel mechanism of action there is also a potential for enhanced therapeutic benefit by combining CB-1158 with other immune checkpoint inhibitors. Citation Format: Matthew Gross, Jason Chen, Ethan Emberley, Julie Janes, Weiqun Li, Andy Mackinnon, Alison Pan, Francesco Parlati, Mirna Rodriguez, Susanne Steggerda, Tracy Wang, Melissa Works, Jing Zhang, Winter Zhang, Mark Bennett. CB-1158 inhibits the immuno-oncology target arginase and causes an immune mediated anti-tumor response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A195.