Colony-stimulating factor-1 (CSF-1) is the primary regulator of mononuclear phagocytic cells. CSF-1 plays an important role in recruiting macrophages to tumor environment. Overexpression of CSF-1 and its ligand, colony-stimulating factor-1 receptor (CSF-1R), have been reported to be associated with the development of various types of cancers, such as breast, ovarian, and colorectal cancer. This study aims to investigate the treatment effects of a new CSF-1R inhibitor named C019199 in murine breast cancer (BC) models when administered alone or in combination with anti-PD-1 antibody.
Inhibition of CSF-1R was investigated in the murine bone marrow derived macrophages (BMDMs) for cell-based assay. Furthermore, the immunocompetent Balb/c mice were subcutaneously implanted 4T1 breast cancer cells in the right flank. Mice were randomized into groups of 9 and treated with C019199 (orally, 30 mg, 60mg or 120 mg/kg/d), either alone or in combination with anti-mouse PD-1 antibody (intraperitoneally, 10 mg/kg). 1 of 9 groups was treated with single-agent Docetaxel (intraperitoneally, 10 mg/kg). The animal body weight and tumor growth were monitored twice a week. Results were analyzed by 2-way ANOVA with Bonferroni's test.
1. C019199 inhibited the murine colony-stimulating factor-1 receptor (CSF-1R) with an IC50 of about 8.0nM in cell-based assay. 2. C019199 inhibited tumor growth in murine BC models. The combination of C019199 and anti-PD-1 had better synergistic antitumor efficacy than single-agent. Balb/c mice implanted 4T1 cells were treated with C019199 alone or combined with anti-PD1 for 14 days. The antitumor efficacy and treatment detail (Table) were detected. Effect of C019199 on body weight and tumor size in murine 4T1 breast cancer models *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 compared with vehicle group. SEM, standard error of mean.
Group Administration regimen Tumor size (mm3,Mean±SEM) Rate% of average body weight change Day 0 Day 14 Vehicle QD x 14 67.11 ± 3.01 1705.69 ± 130.96 13.76% Anti-mPD-1 Day 0, 3, 7, 10 66.82 ± 3.05 1343.55 ± 118.65 16.43% Docetaxel Day 0, 7 66.88 ± 3.11 1023.00 ± 68.19**** 4.21% C019199 QD x 14 67.07 ± 3.17 1074.32 ± 59.31**** 11.01% C019199 QD x 14 66.76 ± 3.05 927.24 ± 65.68**** 7.97% C019199 QD x 14 66.69 ± 2.99 671.71 ± 62.56**** 2.18% Anti-mPD-1 Day 0, 3, 7, 10 66.62 ± 2.94 1079.65 ± 64.05**** 13.25% C019199 QD x 14 Anti-mPD-1 Day 0, 3, 7, 10 66.53 ± 2.86 794.21 ± 105.82**** 10.50% C019199 QD x 14 Anti-mPD-1 Day 0, 3, 7, 10 66.41 ± 2.72 619.62 ± 25.10**** 4.85% C019199 QD x 14
C019199 is a new tyrosine kinase inhibitor of CSF-1R. Single-agent C019199 showed dose-dependently inhibition in murine 4T1 BC tumors. C019199 combined with anti-PD-1 had better antitumor efficacy than C019199 alone. Assessed by animal body weight, such combination therapy was well tolerated. The mechanisms of C019199-mediated immunomodulatory effects in combination with anti-PD-1 need further exploration.
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