Mechanisms Behind Immunotherapy Resistance Discovered

Increased levels of tumor-associated myeloid cells reduce cancer cell sensitivity to treatments.

Investigators recently discovered how an investigational drug can reverse suppressive immune cell activity in patients with cancer.

In a study published by Nature, researchers found that suppressive immune cells interfere with checkpoint inhibitors, which are intended to prevent the body from preventing an immune system attack on cancer cells. Checkpoint inhibitors effectively prevent the body from putting on the “brakes” to prevent an immune attack.

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

The team of investigators used mouse models of cancer to determine whether the effects of TAMCs can be reversed by targeted cancer treatments. The researchers started off by using a growth stimulant to increase TAMCs in mouse models of melanoma to illustrate how these cells are involved with checkpoint inhibitor resistance.

Increased numbers of TAMCs were found to make the melanoma tumor resistant to treatment with checkpoint inhibitors.

Once this relationship was determined, the investigators examined whether blocking immune suppressor cell activity could improve the response to treatment with a checkpoint inhibitor. They used IPI-549 to test their hypothesis.

IPI-549 is an investigational drug that blocks the PI3 kinase-gamma molecule that is located in the suppressor cells. Blocking PI3-kinase gamma decreases the amount of immune suppressor cells and increases immune activation, according to the study.

The drug, owned by Infinity Pharmaceuticals, will be evaluated in combination with Pfizer’s checkpoint inhibitor, Opdivo (nivolumab), in an alliance to determine the safety and efficacy of a combination treatment. The ongoing phase 1 study is also evaluating the safety of IPI-549 prior to conducting any combination treatment studies.

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

They discovered that treatment with IPI-549 significantly increased the response to checkpoint inhibitors in tumors with high levels of TAMCs. When mice with suppressed tumors were treated with checkpoint inhibitors, 20% achieved complete remission.

However, when the drugs were administered with IPI-549, 80% of the mouse models achieved complete remission. IPI-549 was not seen to provide benefit to tumors that lacked the suppressor cells, the investigators said.

The researchers also discovered tumors that initially responded to treatment with checkpoint inhibitorswere then unresponsive if TAMC levels were increased by growth stimulants.

These findings show that TAMCs promote checkpoint inhibitor resistance, and the drug IPI-549 can reverse this effect. Investigators believe that these findings may lead to a novel precision medicine approach to cancer treatment.

“We can now potentially identify patients whose tumors possess immune suppressor cells and add a drug to their treatment regimen to specifically disarm them,” Dr Merghoub concluded.