L-arginine is a critical metabolite for T-cell receptor signaling and subsequent T-cell proliferation, and depletion of arginine arrests T-cell growth. In the tumor microenvironment, infiltrating myeloid-derived suppressor cells (MDSCs), macrophages, and neutrophils produce arginase, which depletes local arginine concentrations and dampens T cell-mediated immune surveillance. Pharmacological inhibition of arginase is expected to restore arginine levels and allow T-cells to proliferate, thereby leading to an immune-mediated anti-tumor response. CB-1158 is a potent inhibitor of human arginase (IC50 = 98 nM). In culture, human granulocytes release arginase and deplete media arginine to levels that inhibit T-cell proliferation. In a co-culture system of human granulocytes and T-cells, CB-1158 potently blocks granulocyte-derived arginase activity, maintains extracellular arginine levels, and restores proliferation of T-cells.
CB-1158 has high oral bioavailability in rodents and is very well tolerated. BID oral dosing of CB-1158 leads to dose-dependent pharmacodynamic increases in plasma and tumor arginine levels resulting in single agent anti-tumor efficacy in mouse syngeneic tumor models including Lewis Lung carcinoma (LLC) and Madison 109. The anti-tumor effects of CB-1158 are consistent with promoting a proinflammatory tumor microenvironment. Following CB-1158 treatment, multiple Th1 T-cell, NK-cell, and M1 macrophage-associated chemokines, cytokines, and activation markers are elevated in the LLC tumor microenvironment. The anti-tumor efficacy of CB-1158 requires an intact tumor microenvironment since CB-1158 has no effect on LLC cell growth in vitro. Furthermore, CB-1158 treatment of immunocompromised C57/SCID mice bearing LLC tumors has no anti-tumor effect, supporting an immune-mediated anti-tumor mechanism.
Immunosuppression in the tumor microenvironment can occur via multiple mechanisms, including arginine depletion, and our data support the combination of checkpoint inhibitors and arginase inhibition by CB-1158. In mice bearing LLC tumors, CB-1158 in combination with checkpoint inhibitors reduced tumor growth, increased the number of tumor infiltrating CD8+ T-cells, and increased the level of Th1/NK/M1-associated chemokines, cytokines, and activation markers in the tumor microenvironment. In mice bearing 4T1 tumors, a tumor type that is highly refractory to checkpoint inhibition, the combination of CB-1158 with anti-PD-1 and anti-CTLA-4 reduces tumor growth and lung metastases. These results support the development of CB-1158, a first-in-class arginase inhibitor, as a novel immuno-oncology agent targeting the immunosuppressive effects of tumor-infiltrating myeloid cells.
Citation Format: Melissa Works, Mark Bennett, Jason Chen, Ethan Emberley, Tony Huang, Julie Janes, Weiqun Li, Andy Mackinnon, Gisele Marguier, Silinda Neou, Alison Pan, Francesco Parlati, Mirna Rodriguez, Susanne Steggerda, Tracy Wang, Jing Zhang, Winter Zhang, Matthew Gross. Immuno-oncology agent CB-1158 is a potent and selective arginase inhibitor and causes an immune-mediated anti-tumor response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 552.