Targeting immunosuppressive myeloid cells within tumors with the PI3k-gamma inhibitor IPI-549 may be a way of preventing immune evasion by cytotoxic T-cells, according to a recent study published in Nature.
The study, “Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells,” shows that such immunosuppressive cells are linked to immune checkpoint inhibitor resistance, suggesting that the IPI-549 treatment may improve the efficacy of immune checkpoint blocking therapies in patients with high levels of myeloid cell infiltration in their tumors.
“Though checkpoint inhibitors have durable effects when they work, not all patients respond to the treatment,” Taha Merghoub, an investigator at the Ludwig Memorial Sloan Kettering Collaborative Laboratory, who led the study with director Jedd Wolchok, said in a press release. “Part of the reason for this is that some tumors harbor tumor-associated myeloid cells, or TAMCs, that prevent T cells from attacking tumor cells.”
To address whether TAMCs are indeed associated with resistance to checkpoint blockade therapies, the researchers used multiple mouse models of cancer. They found that breast cancer mouse models, which exhibited high levels of infiltrating myeloid cells, had lower infiltration of cancer-killing T-cells and, for this reason, were resistant to anti-PD-1 or anti-CTLA4 therapy. Melanoma mouse models, in contrast, had lesser myeloid cell infiltration and increased infiltration of activated T-cells, and were more responsive to immune checkpoint inhibitors.
Next, to assess whether this could be reversed in melanoma models as a way of testing the association, researchers used a specific growth factor, GM-CSF, to increase myeloid cell infiltration into tumors. “We were able to make a tumor that was not rich in immune suppressing myeloid cells into one that was,” said Merghoub. Importantly, these mice were also less responsive to immune checkpoint inhibitors.
The investigators then hypothesized that blocking the activity of these myeloid immunosuppressive cells would improve the animals’ response to checkpoint inhibitors. They used Infinity Pharmaceuticals’ PI3k-gamma inhibitor IPI-549, which is currently being tested in a Phase 1 clinical trial (NCT02637531) in people with advanced solid tumors.
PI3k-gamma is known to play an important role in immune cell function and migration, and seems to support myeloid cells within the tumor microenvironment. By blocking PI3k-gamma, IPI-549 can push these myeloid cells into a pro-inflammatory state, which enhances the recruitment and activation of cytotoxic T-cells.
“We effectively reprogrammed the TAMCs, turning them from bad guys into good guys,” Merghoub said.
Their findings revealed that IPI-549 treatment in mice whose tumors had high infiltration of myeloid cells markedly improved their responses to immune checkpoint inhibitors. Indeed, while only 20 percent of mice treated with immune checkpoint inhibitors achieved complete remission, adding IPI-549 to those therapies induced complete remission in 80 percent of the animals.
This benefit was only seen in tumors with high infiltration of myeloid cells, suggesting that a patient’s tumor profile need be taken into account when deciding whether IPI-549 should be added into a treatment regimen.
“We can now potentially identify patients whose tumors possess immune suppressor cells and add a drug to their treatment regimen to specifically disarm them,” Merghoub said.