39P - CSF-1R inhibitor (C019199) enhances antitumor effect in combination with anti-PD-1 therapy on murine breast cancer models

Background

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.

Methods

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.

Results

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. Table: 39P

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.

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.