Targeting the immunosuppressive activity of tumor-infiltrating myeloid cells, CB-1158, an orally-administered small molecule inhibitor of myeloid cell-derived arginase 1, rescued T cell proliferation in vitro and reduced tumor growth in mice when used alone or with other therapies. CB-1158 prevented the depletion of L-arginine, which is required for T cell proliferation, increasing tumor-infiltrating CD8+ T and NK cells, inflammatory cytokines, and expression of interferon-inducible genes. A clinical trial for patients with solid tumors is ongoing.
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.
Author Info: (1) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. ssteggerda@calithera.com. (2) Calithera Biosciences, 343 Oyster Point Bouleva
Author Info: (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) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (4) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (5) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (6) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (7) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (8) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (9) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (10) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (11) Max Planck Institute for Biochemistry, Martinsried, Germany. Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (12) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (13) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (14) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (15) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (16) Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (17) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (18) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (19) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (20) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. (21) Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA.
