Protein may predict response to immunotherapy for melanoma

Volume 5, Issue 1, 2016

Summary

The discovery of biomarkers of sensitivity to treatment is vital for informing clinical decisions.

Photograph of Roxana S. Dronca, M.D.

Roxana S. Dronca, M.D.

Mayo Clinic Cancer Center researchers have identified a protein marker whose frequency may predict how patients respond to PD-1 blockade immunotherapy for melanoma.

Their findings were presented at the Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival in New York City in September 2015.

"The discovery of biomarkers of sensitivity to treatment is vital not only for informing clinical decisions, but also for identifying which patients with melanoma, and possibly other malignancies, may be most likely to benefit from PD-1 blockade," said Roxana S. Dronca, M.D., a Mayo Clinic Cancer Center hematologist. "This will allow us to expose fewer patients to inadequate treatment and the associated toxicities and costs."

The protein marker called Bim helps coordinate programmed cell death, a natural process that occurs in many cells, including T cells, and a subset of immune cells that can recognize and kill tumor cells. Interaction of a molecule called PD-1 on T cells with a molecule called PD-L1 activates Bim and can induce T cell death.

Tumors can exploit the process of cell death by overexpressing PD-L1 and killing T cells that could recognize and eliminate them.

In an effort to overcome the problem of tumors evading the immune system, Dr. Dronca and her colleagues generated biological molecules that block PD-1 from interacting with PD-L1. These PD-1 blockers have shown promising results in some patients with cancer, but not others — prompting a search for markers that could predict how patients will respond to the molecules before treatment.

"If I know that a patient has a very high likelihood of responding to anti-PD-1 therapy, I'm going to be more inclined to recommend that treatment and feel better about the choice," Dr. Dronca said.

Researchers also found that patients with metastatic melanoma who responded to PD-1 blockade with pembrolizumab had more tumor-targeting T cells expressing Bim and PD-1 in their blood prior to therapy than did patients who did not respond. They also observed that this trend reversed after weeks of treatment, suggesting that proportions of these cells can be measured to help clinicians decide which patients should and should not be treated with PD-1 blockade.

"Responders also had higher levels of soluble PD-L1 in their blood prior to treatment," Dr. Dronca said. "This suggests that PD-1 blockade is most effective when the PD-1-PD-L1 interaction plays a major role in disease."