Experimental Drug May Overcome Cancer Treatment Resistance

The experimental drug IPI-549 was found to reverse the effects of tumor-associated myeloid cells (TAMCs) that prevent the immune system from attacking tumors.

In a study published in Nature, researchers used mouse models of cancer to demonstrate that the effects of TAMCs can be reversed by a targeted therapy.

“Though checkpoint inhibitors have durable effects when they work, not all patients respond to the treatment,” said co-lead researcher Taha Merghoub. “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.”

For the study, researchers wanted to demonstrate that TAMCs play a role in the resistance to checkpoint blockades. To illustrate this effect, the researchers used a specific growth stimulant to increase the number of melanoma tumors, in order to create a workable model for the study. By doing so, the researchers found the tumors were subsequently less susceptible to treatment with the checkpoint blockade.

“We were able to make a tumor that was not rich in immune suppressing myeloid cells into one that was,” Merghoub said.

After establishing the link between checkpoint inhibitor resistance and TAMCs, researchers wanted to test whether blocking immune suppressor cell activity improves the response to immunotherapy.

The researchers decided to use the experimental drug IPI-549, because it blocks the molecule PI3 kinase-gamma, which causes the balance of immune suppressor cells to change in favor of greater immune system activity.

“We effectively reprogrammed the TAMCs, turning them from bad guys into good guys,” Merghoub said.

The researchers found that in tumors with high concentrations of TAMCs, IPI-549 dramatically improved the response to immune checkpoint blockade (ICB) therapy. When researchers administered the checkpoint inhibitors to mice with suppressed tumors, they found that only 20% of the rodents achieved complete remission. However, when the same drugs were co-administered with IPI-549, it jumped to 80%.

The authors noted that IPI-549 provided no benefit to tumors that lacked the suppressor cells.

The researchers were also able to demonstrate that the tumors that were initially sensitive to checkpoint inhibitors became unresponsive when their TAMC concentrations became boosted with growth stimulants.

When taken together, however, the findings showed that TAMCs promote resistance to checkpoint inhibitors. They also found thatIPI-549 can selectively block these cells, enabling them to overcome this resistance.

“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.

In the United States, IPI-549 is currently undergoing a phase 1 trial.