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How Advanced Melanoma Resists Immunotherapy

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Image illustrates how a cancer cell expresses programmed-death ligand 1 by secreting interferon gamma in response to immune-cell attack. Image: Courtesy of Dr. Antoni Ribas

A new study by scientists at the UCLA Jonsson Comprehensive Cancer Center could be a significant step toward understanding how certain cases of advanced melanoma shield themselves from pembrolizumab, the U.S. Food and Drug Administration (FDA)-approved treatment that harnesses the immune system to attack the disease.

The research, led by Antoni Ribas, MD (FEL ’98, ’01), PhD, director of the immunotherapy program at the UCLA Jonsson Comprehensive Cancer Center, studied how melanoma cancer cells react to the interferon gamma pathway, which guides cell signaling and can affect the way cancer cells react to pembrolizumab. The team then discovered and mapped out the molecules involved in the signaling pathway. The findings lay the groundwork for developing new and improved combination therapies for patients who are resistant to stand-alone immunotherapy treatments.

Pembrolizumab works by signaling the patient’s immune system to recognize and attack cancer cells, with minimal side effects. The FDA approved the drug in 2014 to treat advanced melanoma and, more recently, to treat people with advanced non-small cell lung cancer. The medication is currently being tested as a treatment for other types of cancer.

In February 2017, a study published by Dr. Ribas and colleagues showed that people with cancers containing genetic mutations JAK1 or JAK2 (which are known to prevent tumors from recognizing or receiving signals from T-cells to stop growing) will receive little or no benefit from pembrolizumab. This discovery enabled the scientists to determine why some people with advanced melanoma or colon cancer will not respond to the drug.

That built on 2016 research by Dr. Ribas and colleagues, in which they analyzed pairs of tumors both before a patient had undergone immunotherapy treatment and after relapse. The results showed that one of the tumors lost a gene called B2M, which resulted in a change in how the cancer is recognized by the immune system. The disruption caused JAK1 and JAK2 to function improperly and prevented the immune system from attacking the cancer.

The new study was conducted over a two-year period; the scientists analyzed dozens of melanoma cell lines and several tumor samples from patients. In the laboratory, researchers also used an advanced technology called a lentivirus shRNA screen to locate which molecules were involved in the interferon-receptor-pathway-signaling process. The research allows further investigations into how the immune systems of patients with advanced cancers can resist anti–PD-1 immunotherapy treatments, the class of treatments that includes pembrolizumab.

“Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression,” Cell Reports, May 9, 2017

 





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