In this study, Guerriero demonstrated that suppressive macrophages have high levels of CSF-1R, and that PARP inhibitors further increased expression of CSF-1R. Anti-CSF-1R therapy can deplete a subset of macrophages, primarily tumor-promoting macrophages, Guerriero said.

Based on these observations, the researchers also tested the effects of using either an anti-CSF-1R antibody or olaparib or a combination of both in a BRCA-mutated TNBC mouse model. Whereas the anti-CSF-1R antibody was not active as a single-agent, olaparib was found to extend the median overall survival from 22 days to 92 days, which further increased to 190 days when anti-CSF-1R was combined with olaparib therapy.

“This may not mean much to the general public, but extending the overall survival by 100 days in a mouse model is really exciting,” Guerriero said.


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Targeting the CSF-1 pathway had been of potential interest as a method of restricting tumor growth for about 20 years, Ruffell added.

“There are several good drugs that target CSF-1R, including small molecular inhibitors and an antibody that works by blocking receptor dimerization,” Ruffell said. “The barrier has been that the drugs don’t seem to work as single agents.”

Many initial clinical trials failed for 1 of 2 reasons, he said. First, the therapies had no efficacy as single agents. Second, these drugs have shown signs of liver toxicity in some patients.

“Macrophages are in every organ of your body and some trials have observed liver toxicity when the CSF-1R inhibitors are used in combination,” Ruffell said.

One of the goals of their research has been to convert pro-tumor macrophages to an anti-tumor phenotype, Guerriero explained.

“Unlike T cells, macrophages only have a 4 to 5-day lifespan,” she said. “The goal is to eliminate the suppressive macrophages within the tumor so that the tumor microenvironment becomes less suppressive and T cells and new antitumor macrophages can come in.”

This study identified a niche where the PARP inhibitor is making the macrophages express CSF-R1, Guerriero explained.

“While other macrophages in tissue do express CSF-1R, we think that by the PARP inhibitors turning on CSF-1R within the tumor macrophages, we can directly target the tumor macrophages and spare macrophages in other tissues and organs,” she said.

Ruffell said that the survival advantages seen in this mouse study were quite strong, and CSF-1R inhibition appears to be a promising approach to use with BRCA-targeted therapies.

More interesting, he said, will be the next steps.

“How well CSF-1R inhibitors will work in clinic is unclear,” Ruffell said. “Ideally, we will find ways to change macrophage function. If we can more specifically target tumor macrophages we can unleash the positive side of the cells and hopefully see better responses to therapy.”

Disclosures: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the original study.

Reference

Mehta AK, Cheney EM, Hartl CA, et al. Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer. Published online December 14, 2020. doi:10.1038/s43018-020-00148-7