CX-1158-101: A First-in-Human Phase 1 Study of CB-1158, a Small Molecule Inhibitor of Arginase, as Monotherapy and in Combination with an anti-PD-1 Checkpoint Inhibitor in Patients with Solid Tumors Kyriakos Papadopoulos 1 , Frank Tsai 2 , Todd Bauer 3 , Lucas Muigai 4 , Yu Liang 4 , Mark Bennett 4 , Keith Orford 4 , Siqing Fu 5 1 South Texas Accelerated Research Therapeutics (START), San Antonio, TX; 2 Pinnacle Oncology Hematology, Phoenix, AZ; 3 Sarah Cannon Research Institute/Tennessee Oncology, PLLC., Nashville, TN, 4 Calithera Biosciences, South San Francisco, CA; 5 MD Anderson Cancer Center, Houston, TX
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CX-1158-101: A First-in-Human Phase 1 Study of CB-1158, a ...€¦ · CX-1158-101: A First-in-Human Phase 1 Study of CB-1158, a Small Molecule Inhibitor of Arginase, as Monotherapy
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CX-1158-101: A First-in-Human Phase 1 Study
of CB-1158, a Small Molecule Inhibitor of
Arginase, as Monotherapy and in Combination
with an anti-PD-1 Checkpoint Inhibitor in
Patients with Solid Tumors
Kyriakos Papadopoulos1, Frank Tsai2, Todd Bauer3, Lucas Muigai4, Yu
Liang4, Mark Bennett4, Keith Orford4, Siqing Fu5
1South Texas Accelerated Research Therapeutics (START), San Antonio, TX; 2Pinnacle Oncology
Hematology, Phoenix, AZ; 3 Sarah Cannon Research Institute/Tennessee Oncology, PLLC., Nashville, TN, 4Calithera Biosciences, South San Francisco, CA; 5MD Anderson Cancer Center, Houston, TX
Immunosuppression in the Tumor
Microenvironment
• Despite the important advances in immunotherapy, a limited number of
patients derive significant benefit from checkpoint inhibitors
• Tumor-infiltrating myeloid cells suppress T-cell and NK cell function and can
limit the activity of checkpoint inhibitors
• Arginase is a key immunosuppressive enzyme secreted by tumor-infiltrating
myeloid cells
• Inhibiting arginase offers a novel strategy to relieve immunosuppression and
to enhance checkpoint inhibitor activity
• CB-1158 is a first-in-class oral arginase inhibitor in a Phase 1 clinical study
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Arginase in Cancer Patients
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Arginase-positive myeloid cell
infiltrate in tumor tissues
High arginase and low
arginine in patient plasma
Plasma
Arginase
Plasma
Arginine
HNSCC
Arginase 1
H&E
Head and Neck tumor
Arginase-Mediated Immune Suppression
in Tumor Microenvironment
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Arginine is
required for
proliferation of
activated CD8+
T-cells
Arginase depletes
arginine in tumor T-cell/
NK cell
↓ proliferation
↓ TCRz
↓ IFNg
MDSC/
Neutrophil Low Arginine Arginase
Arginase Assay CB-1158 IC50
Arginase 1 (recombinant) 98 nM
Reversal of neutrophil-mediated T-cell suppression 200 nM
CB-1158
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CB-1158 Inhibits Arginase and
Overcomes T-cell Suppression Arginase inhibition
increases arginine T-cell/
NK cell
↑ proliferation
↑ TCRz
↑ IFNg
MDSC/
Neutrophil High Arginine Arginase
CB-1158 Has Single Agent and Combination
Activity in Syngeneic Tumor Models
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Increased
CD8+ TILs
Monotherapy anti-tumor activity
LLC (Lung)
Combination anti-tumor activity
with checkpoint inhibitor
Increased plasma and tumor arginine
CT26 (Colon)
Plasma Tumor (LLC)
CX-1158-101 Phase 1 Study Objectives • Primary
– Evaluate the safety and tolerability of CB-1158 in patients with