1. Academic Validation
  2. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment

Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment

  • J Immunother Cancer. 2017 Dec 19;5(1):101. doi: 10.1186/s40425-017-0308-4.
Susanne M Steggerda 1 Mark K Bennett 2 Jason Chen 2 Ethan Emberley 2 Tony Huang 2 Julie R Janes 2 Weiqun Li 2 Andrew L MacKinnon 2 Amani Makkouk 2 Gisele Marguier 2 Peter J Murray 3 4 Silinda Neou 2 Alison Pan 2 Francesco Parlati 2 Mirna L M Rodriguez 2 Lee-Ann Van de Velde 4 Tracy Wang 2 Melissa Works 2 Jing Zhang 2 Winter Zhang 2 Matthew I Gross 2
Affiliations

Affiliations

  • 1 Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. ssteggerda@calithera.com.
  • 2 Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA.
  • 3 Max Planck Institute for Biochemistry, Martinsried, Germany.
  • 4 Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Abstract

Background: Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme Arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small-molecule inhibitor of Arginase, to investigate the role of Arg1 in regulating anti-tumor immunity.

Methods: CB-1158 was tested for the ability to block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for tumor growth inhibition in syngeneic mouse models of Cancer as a single agent and in combination with other therapies. Tumors from Animals treated with CB-1158 were profiled for changes in immune cell subsets, expression of immune-related genes, and cytokines. Human tumor tissue microarrays were probed for Arg1 expression by immunohistochemistry and immunofluorescence. Cancer patient plasma samples were assessed for Arg1 protein and L-arginine by ELISA and mass spectrometry, respectively.

Results: CB-1158 blocked myeloid cell-mediated suppression of T cell proliferation in vitro and reduced tumor growth in multiple mouse models of Cancer, as a single agent and in combination with checkpoint blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158 increased tumor-infiltrating CD8+ T cells and NK cells, inflammatory cytokines, and expression of interferon-inducible genes. Patient tumor samples from multiple histologies expressed an abundance of tumor-infiltrating Arg1+ myeloid cells. Plasma samples from Cancer patients exhibited elevated Arg1 and reduced L-arginine compared to healthy volunteers.

Conclusions: These results demonstrate that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that Arginase blockade by CB-1158 may be an effective therapy in multiple types of Cancer and combining CB-1158 with standard-of-care chemotherapy or other immunotherapies may yield improved clinical responses.

Keywords

Arg1; Arg2; Arginase; Arginine; Checkpoint blockade; Granulocyte; Immunotherapy; Myeloid derived suppressor cell; Tumor associated macrophage; Tumor microenvironment.

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