Arginase Inhibitor CB-1158 Inhibits Tumor Growth by Increasing Activated T-cells in the Tumor Microenvironment
Susanne Steggerda, M. Bennett, J. Chen, E. Emberley, M. Gross, T. Huang, W. Li, A. MacKinnon, A. Makkouk, G. Marguier, S. Neou, A. Pan, T. Wang, J. Zhang, W. Zhang and F. Parlati
Calithera Biosciences Inc., South San Francisco, California
Myeloid cells contribute to an immunosuppressive tumor microenvironment by releasing the enzyme arginase, which depletes extracellular arginine. In human tumors, arginase-expressing granulocytic infiltrates are abundant in multiple tumor types. In cancer patient plasma, we found significantly higher levels of arginase and lower levels of arginine compared to healthy volunteers. CB-1158 is an orally-bioavailable, potent, and specific inhibitor of human arginase (IC50=100 nM). In a co-culture of human T-cells with granulocytes or MDSCs, CB-1158 reversed suppression of T-cell proliferation and inflammatory cytokine production by blocking arginine depletion. In multiple syngeneic mouse models, CB-1158 increased tumor and plasma arginine levels and had single-agent anti-tumor activity at doses that were well-tolerated. In the tumor, treatment with CB-1158 increased pro-inflammatory cytokines and chemokines, increased expression of T-cell and NK-cell markers, and increased tumor infiltration of activated CD8 T-lymphocytes. CB-1158 treatment enhanced the anti-tumor efficacy of adoptive T-cell therapy, checkpoint inhibition, and gemcitabine chemotherapy in combination regimens. In a phase 1 clinical trial for patients with solid tumors, early data show CB-1158 is well-tolerated. At the first dose level of 50 mg BID, trough exposure of >1 M and up to a 2.7-fold elevation in normalized plasma arginine levels have been measured. Increases in arginine levels in patients demonstrate on-target arginase inhibition and support the further clinical development of CB-1158 for the treatment of cancer.
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