UCLA Team Learns Why Some Cancers Stop Responding to Immunotherapy

Discovery opens way to improved treatments

Researchers at the University of California, Los Angeles, have identified mechanisms that determine how advanced melanoma can become resistant to immune checkpoint inhibitors, a discovery that could lead to the development of new and improved treatments for the deadliest type of skin cancer.

Immunotherapy using the anti–programmed death-1 antibody pembrolizumab has revolutionized the treatment of advanced melanoma. But a minority of patients who respond to treatment still experience the reappearance and progression of their tumors, said Dr. Antoni Ribas, director of the tumor immunology program at UCLA’s Jonsson Comprehensive Cancer Center.

“The tremendous promise of immunotherapy is to engage our body’s immune defenses to fight cancer, but the results must be long-lasting,” Ribas said. “We have now identified for the first time mechanisms that cancer cells can use to avoid recognition by the immune system’s T cells and decrease sensitivity to their attack.”

The study was published online in the New England Journal of Medicine.

The researchers analyzed biopsies of melanoma tumors from patients that received pembrolizumab. The team then compared pairs of tumors taken both before the patients started treatment and after relapse, which occurred several months to years later.

Among the four pairs of biopsies studied, the team found one tumor lost a gene called B2M, resulting in a change in how the cancer is recognized by the immune system. Two additional tumors developed defects that disrupted the function of JAK1 or JAK2 genes, which limited the effectiveness of the immune system to kill cancer cells.

“We discovered that while the immune system’s T cells remained active, new alterations in JAK1 and JAK2 caused the tumor to become selectively deaf to the signals they were sending that normally tell the cancer cells to stop growing, while genetic changes in B2M decreased the ability of the immune system to recognize the cancer in the first place,” said first author Jesse Zaretsky, a doctoral student. “These findings can help open up a whole new potential area of research and allow us to better understand acquired resistance to these promising treatments.”

The team also found a fourth pair of biopsies that did not have either of these genetic variations, which indicates that other mechanisms to escape immunotherapies may be discovered in the future, Zaretsky said.

The researchers plan to develop preclinical models to further examine these genetic alterations.

As scientists learn what the mechanisms of tumor resistance are, they can combine inhibitor drugs that block multiple resistance routes and eventually make the tumors shrink for much longer, or go away completely, Ribas said.

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