A CSF1R-Targeting Antibody Inhibits Tumor-Associated Macrophages

Tumor-associated macrophages (TAM) promote angiogenesis and enhance immunosuppression in various solid tumors, and have been associated with poor prognosis. Survival of TAMs is mediated by signaling through colony-stimulating factor 1 receptor (CSF1R), suggesting that targeted blockade of this receptor may limit tumor growth and progression. To test this hypothesis, Ries and colleagues generated a high-affinity, humanized anti-CSF1R monoclonal antibody (RG7155) that inhibited both ligand-dependent and ligand-independent activation of CSF1R by impairing receptor dimerization. Treatment with anti-CSF1R antibody selectively induced apoptosis of CSF1R⁺CD163⁺ M2-like macrophages but not CD80⁺ M1-like macrophages in vitro and depleted TAMs in tumor-bearing mice. In addition, CSF1R blockade resulted in a relative increase in cytotoxic effector CD8⁺ T cells and a decrease in CD4⁺FOXP3⁺ regulatory T cells and delayed tumor growth and metastasis in mouse models of colorectal adenocarcinoma and fibrosarcoma. Consistent with this finding, RG7155 treatment significantly diminished CSF1R⁺CD163⁺ TAMs and triggered a shift toward an increased CD8/CD4 T-cell ratio in patients with advanced solid tumors. Furthermore, in a phase I trial, administration of RG7155 resulted in objective clinical responses and symptomatic improvement in patients with diffuse-type giant cell tumor, a disease that affects large joints and is driven by CSF1 overexpression; this clinical activity was associated with a reduction in intratumoral CSF1R⁺CD163⁺ macrophages. Together with studies on other CSF1R antibodies and small-molecule inhibitors, these results identify targeting of TAMs as a promising therapeutic strategy in various solid tumors and support testing of CSF1R blockade in combination with standard of care chemotherapeutic agents and immunotherapies.

Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti–CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014 Jun 1 [Epub ahead of print].