Arginase inhibitor CB-1158 elicits immune-mediated anti-tumor responses as a single agent and enhances the efficacy of other immunotherapies

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S97-S97
• Main Authors: Steggerda, S, Bennett, M, Chen, J, Emberley, E, Gross, M, Huang, T, Li, W, MacKinnon, A, Makkouk, A, Marguier, G, Neou, S, Pan, A, Wang, T, Works, M, Zhang, J, Zhang, W, Parlati, F
• Format: Article
• Language: English
• Subjects: Adipocytes; Amino acids; Animal models; Anticancer properties; Antitumor agents; Arginase; Arginine; Bioavailability; Cancer; Cancer immunotherapy; CD8 antigen; Cell activation; Cell culture; Cell proliferation; Cytokines; Effectiveness; Gemcitabine; Hematology, Oncology and Palliative Medicine; Immune response; Immunosuppression; Inhibitors; Ionizing radiation; Leukocytes (neutrophilic); Leukocytes (polymorphonuclear); Liver cancer; Lung carcinoma; Lymphocytes T; Melanoma; Mice; Molecular chains; Myeloid cells; Natural killer cells; Patients; PD-L1 protein; Pharmacodynamics; Pharmacology; Radiation dosage; Suppressor cells; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32888-X

Myeloid derived suppressor cells (MDSCs) and polymorphonuclear cells (PMNs) limit effective anti-tumor immune responses; however there are no approved clinical agents that directly antagonize the activity of these cells. One of the immunosuppressive mechanisms of MDSCs and PMNs is the expression and secretion of the enzyme arginase into the tumor microenvironment resulting in local depletion of the amino acid arginine, a key nutrient required by T-cells and natural killer (NK)-cells to proliferate and mount an effective anti-tumor response. To assess the potential of arginase inhibition as a therapeutic strategy, we surveyed the abundance of arginase in tumor and plasma from cancer patients across multiple histotypes. Consistent with previous reports, we observed that multiple tumor types have substantial arginase-expressing PMN infiltrates and that cancer patients have higher levels of plasma arginase and lower levels of plasma arginine compared to healthy controls. CB-1158 is a potent, selective, and orally-bioavailable small molecule inhibitor of arginase (IC50 = 98 nM). In a co-culture system, neutrophils or patient-derived MDSCs strongly suppressed T-cell proliferation. The addition of CB-1158 blocked arginase activity, maintained arginine levels, and allowed T-cells to proliferate in the presence of MDSCs/PMNs, highlighting arginase as a prominent immunosuppressive mechanism of these myeloid cells. CB-1158 has high oral bioavailability in mice and rats. Twice-daily oral dosing of CB-1158 produced dose-dependent pharmacodynamic increases in plasma and tumor arginine levels and resulted in single-agent anti-tumor efficacy in several murine syngeneic tumor models including Lewis Lung carcinoma (LLC), Madison-109 lung carcinoma, and B16F10 melanoma. Immunodepletion of either CD8' T-cells or NK-cells partially antagonized the anti-tumor effect of CB-1158 in the LCC and B16F10 models indicating that the CB-1158 acts by an immune cell-mediated mechanism. Consistent with immune-mediated anti-tumor efficacy, CB-1158 dosing of LLC-tumor bearing mice resulted in increases in tumor infiltrating CD8· T-cells, increased levels of tumor Th1 T-cell cytokines, and increased expression of T-cell and NK-cell activation markers. Based on its novel mechanism of action, there is potential for CB-1158 to enhance the activity of other immunotherapies or standard-of-care therapeutics. We observed improved anti-tumor activity when CB-1158 was combined with either epacadostat