Challenges and prospects of CSF1R targeting for advanced malignancies

Abstract

CSF1R expression modulates tumor-associated macrophages, making CSF1R blockade an appealing immune-modulating therapeutic target. We evaluated the correlation between CSF1R tumor RNA expression and outcome (pan-cancer setting). RNA expression was ranked as a percentile (0-100) using a standardized internal reference population (735 tumors; 35 histologies). Among 514 patients, there was no difference in survival from biopsy between high and low CSF1R expressors (< 50 percentile versus ≥ 50 percentile rank). There was also no significant difference in median progression-free or overall survival (from treatment) based on CSF1R expression in 21 patients who received CSF1R inhibitors (all p values ≥ 0.08). Concurrent upregulation of ≥ 2 additional immune checkpoint markers (e.g. PD-L1, BTLA, CTLA4, LAG3, TIM3) was observed in all tumor samples with CSF1R expression ≥ 50th percentile. Pending further large prospective studies, patients with high tumor CSF1R expression may need treatment that co-targets the specific immune checkpoint pathways activated in order to impact outcome.

Keywords: CSF1R; biomarker; cancer; checkpoints; targeted therapy.

Figure 1

Kaplan-Meier analysis of overall based on RNA expression rank of CSF1R (n = 514). There is no significant difference between mOS based on CSF1R expression rank ≥ 50 percentile (34.05 months) compared to CSF1R < 50 percentile (28.07 months) (P = 0.23) among all patients whose tumor tissue was sent for genomic profiling. Survival is calculated from date of biopsy to date of death or last contact (if patient still alive at last contact, survival was censored on that date).

Figure 2

Kaplan-Meier analysis of progression-free survival and overall survival from initiation of tyrosine kinase inhibitor with CSF1R inhibition based on RNA expression rank of CSF1R. A. Comparison of median PFS between CSF1R 50-74 percentile (3.75 months) and CSF1R < 50 percentile (4.04 months) showed no difference (P = 0.43). B. Median PFS showed a trend towards worse PFS in patients with CSF1R expression ≥ 75 percentile at 1.74 months compared to 4.04 months for CSF1R < 50 percentile (P = 0.08). C. Median PFS was not statistically different between CSF1R < 50 percentile (4.04 months) and CSF1R ≥ 50 (2.56 months) (P = 0.22). D. OS was compared between CSF1R 50-74 percentile (20.51 months) and CSF1R < 50 percentile (13.25 months) with no statistically significant difference (P = 0.64). E. No statistically significant difference in OS was observed based on CSF1R ≥ 75 percentile compared to CSF1R < 50 percentile (5.26 months vs 13.25 months) (P = 0.35). F. Median OS was not significantly prolonged among patients with CSF1R ≥ 50 percentile treated with a CSF1R inhibitor (20.51 months) compared to CSF1R < 50 percentile (13.25 months), although there was a trend toward a longer OS (P = 0.42). ¹(+) indicates censored event.

Figure 3

Expression pattern of multiple checkpoint markers among patients who received tyrosine kinase inhibitor with CSF1R inhibition (N = 21). Numbers indicate RNA expression rank, color coding was based on RNA expression rank of low, intermediate, or high, corresponding to values of 0-24, 25-74, and 75-100 percentile, respectively. Patients with intermediate or high CSF1R expression all demonstrated simultaneous intermediate or high expression of two or more other immune checkpoint proteins.