A mouse study suggests that daily doses of a CSF1R inhibitor after radiation therapy can reduce the likelihood of glioblastoma recurrence. Mice that received the inhibitor lived more than twice as long as control animals, and only 20% of them developed recurrent tumors, whereas all control animals did.

Tumor-associated macrophages (TAM), immune cells that support tumor growth, may promote resistance to radiotherapy and drugs and reduce survival. Long-term treatment with an inhibitor of colony-stimulating factor–1 receptor (CSF1R) prevents activation of these cells and delays glioma recurrence after radiation, a mouse study shows. The approach could improve treatment for patients with glioblastoma.

In brain tumors, TAMs can be resident microglia or peripherally recruited monocyte-derived macrophages (MDM). Whether these two cell populations have different effects on treatment resistance and recurrence—and thus survival—has been unclear.

In the study, Johanna Joyce, PhD, of the University of Lausanne in Switzerland, and colleagues tracked both cell types after radiation therapy in two mouse models of glioma. The researchers discovered that the proportion of the two macrophage types changed in recurrent gliomas. In one model, for instance, MDMs accounted for 30% to 40% of TAMs in untreated tumors, but more than 50% of TAMs in recurrent tumors, suggesting they may be important for tumor regrowth.

The researchers next asked whether excluding MDMs from the brain delays recurrence. They treated both models with radiation and gave some animals in each cohort an antibody that blocks CD49d, a protein that allows immune cells to enter the brain. The antibody enhanced the potency of radiation, boosting survival by 11% in one model and 40% in the other.

Because clinical trials are evaluating several strategies to thwart macrophages in glioblastoma—including inhibitors of CSF1R, a receptor that stimulates the cells to differentiate, survive, and proliferate—Joyce and her team tested whether adding the inhibitor BLZ945 (Novartis) to radiation was effective in the mice. In one model, tumors shrank by 73% in animals that received radiation and BLZ945 for 5 days, versus 54% in the animals that received radiation alone.

On the strength of those results, the scientists investigated whether the combination inhibits recurrence. They first gave some mice both treatments for 5 days and then the drug alone for 7 more days. Mice that received this combination survived for a median of 13.9 weeks, whereas animals that received only radiation lived for a median of 10.2 weeks.

The combo therapy had about the same impact on survival as the antibody that blocks MDM entry into the brain, but the researchers hypothesized that long-term treatment with BLZ945 would be more effective. They gave one mouse model radiation for 5 days and BLZ945 for the 26-week duration of the experiment. Only 20% of the mice treated with the combination developed recurrent tumors during the experiment, all of which were residual or grade II. In contrast, all control animals, which received only radiation, had grade IV recurrent tumors. More than 90% of the mice that received radiation and BLZ945 were alive at the experiment's end, but none of the mice that received radiation alone survived longer than 16 weeks. “To get this striking synergy, we needed to give the inhibitor every day,” Joyce says.

“Overall, this is state-of-the-art science,” says J. Martin Brown, DPhil, of Stanford University School of Medicine in Stanford, CA, who is participating in a clinical trial of a different drug that excludes macrophages from tumors. However, he is skeptical that CSF1R inhibitors will prove useful, noting that when the inhibitor was tested on mice implanted with a human glioblastoma cell line, the benefit was smaller.

In addition, Brown says a 2018 clinical trial that paired the CSF1R inhibitor pexidartinib (Turalio; Daiichi Sankyo) with radiation detected no improvement in overall survival versus historical controls. However, pexidartinib is not as potent as BLZ945, Joyce notes, and the study did not stratify patients, which could explain the results.

Joyce says her team's findings have implications for clinical trials testing CSF1R inhibitors plus standard therapy in glioblastoma. “We need to be thinking about daily dosing” and extending treatment with the inhibitors, if possible, to produce maximal survival, she says, adding that a CSF1R–checkpoint inhibitor combination might also delay recurrence. –Mitch Leslie

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.