Abstract B045: Arginase inhibitor CB-1158 elicits immune-mediated antitumor responses as a single agent and in combination with other immunotherapies

• Published in: Cancer immunology research 2016-11, Vol.4 (11_Supplement), p.B045-B045
• Main Authors: Steggerda, Susanne M., Bennett, Mark, Chen, Jason, Emberley, Ethan, Gross, Matthew, Huang, Tony, Li, Weiqun, MacKinnon, Andy, Makkouk, Amani, Marguier, Gisele, Neou, Silinda, Pan, Alison, Wang, Tracy, Works, Melissa, Zhang, Jing, Zhang, Winter, Parlati, Francesco
• Format: Article
• Language: English
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.IMM2016-B045

Myeloid derived suppressor cells (MDSCs) and polymorphonuclear cells (PMNs) are mediators of tumor immune evasion, however there are no approved clinical agents that directly antagonize the immunosuppressive activity of these cells. One of the mechanisms by which MDSCs and PMNs suppress anti-tumor immunity is expression of the enzyme arginase, which reduces L-arginine levels rendering T-cells and natural killer (NK)-cells unable to proliferate and mount an effective anti-tumor response. As a rationale to pursue arginase inhibition as a potential therapeutic strategy, we investigated the prevalence of arginase in tumors and peripheral blood from patients with various types of cancer. Our results confirm reports that multiple tumor types have arginase-expressing PMN infiltrates and that cancer patients have higher levels of plasma arginase and lower levels of plasma arginine compared to healthy volunteers. We also confirmed that in vitro-activated primary human T-cells and NK-cells require arginine to proliferate, secrete pro-inflammatory cytokines, and express the intracellular signaling molecule CD3ζ and cell surface activation marker PD-1. We developed CB-1158 to be a potent, selective, and orally-bioavailable small molecule inhibitor of arginase. CB-1158 potently inhibits recombinant human arginase 1 (IC50 = 98 nM), recombinant human arginase 2 (IC50 = 249 nM), and endogenous arginase from human neutrophils (IC50 = 160 nM). In a co-culture system, neutrophils strongly suppressed T-cell proliferation. The addition of CB-1158 blocked arginase activity, maintained arginine levels in the media, and allowed T-cells to proliferate in the presence of suppressive myeloid cells, suggesting that arginase is a major mechanism of myeloid cell suppression of lymphocyte proliferation and that CB-1158 can reverse the suppression. To extend these findings to MDSCs, we isolated peripheral monocytic MDSCs (M-MDSCs) or granulocytic MDSCs (G-MDSCs) from cancer patients and found that G-MDSCs expressed higher levels of arginase, depleted more arginine from cell-culture media, and were more suppressive to T-cell proliferation compared to M-MDSCs. Incubation of G-MDSCs with CB-1158 resulted in media arginine levels that could support T-cell proliferation. 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