Immunotherapies have revolutionized the treatment of advanced melanoma treatment, but some patients who initially respond still experience tumor reappearance and progression. Now, the mechanisms through which advanced melanoma acquires resistance to immune checkpoint inhibitors is starting to be unveiled by researchers at University of California, Los Angeles.
Their work, published in The New England Journal of Medicine and titled “Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma,” may lead to the development of new treatments that prolong remission periods or eliminate tumors.
“The tremendous promise of immunotherapy is to engage our body’s immune defenses to fight cancer, but the results must be long-lasting,” Dr. Antoni Ribas, a professor of hematology and oncology, and director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, said in a press release. “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 team, led by Ribas, foccused on patients who responded to the anti-PD-1 antibody Keytruda (pembrolizumab) but eventually relapsed while on the immunotherapy. Recently, a study revealed that 25 percent of melanoma patients who objectively responded to PD-1 blockade therapy showed disease progression at a median follow-up of 21 months.
To understand how the cancer becomes resistant, the team analyzed four pairs of tumor biopsies, collected before patients started treatment and again after they relapsed, which occurred months to years later.
Researchers found that one of the tumors had lost the expression of B2M, a gene involved in the recognition of tumor cells by the immune system. Two other tumors had mutations that disrupted the function of the JAK1 and JAK2 genes, which reduced the immune system effectiveness 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 Jesse Zaretsky, the study’s first author. “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 fourth pair did not exhibit any of these mutations, meaning that other genetic variations may be involved in the acquired resistance to immunotherapy. Identifying these alterations is important because it may lead to the development of combined therapies that target multiple pathways in the cells, allowing for improved outcomes.