Researchers at Tel Aviv University and Sheba Medical Center say they have discovered a reason for why more than half of patients with metastatic melanoma do not respond to immunotherapy cancer treatments, which harness the immune system cells in targeting the disease.
Melanoma is the most dangerous type of skin cancer. It accounts for only about 1 percent of skin cancers, but causes a large percentage of skin cancer deaths, according to the American Cancer Society. The rates of the cancer have been on the rise in the past 30 years, with 7,230 people expected to die of melanoma in the United Sstates this year. Metastatic melanoma is when the cancer has spread to other places in the body.
In a study published in in Cell earlier this month, the Israeli researchers report that they have found that patients who do not respond to immunotherapy treatments — when the body’s own immune system is used to control and eliminate cancers — tend to have lower fatty acid metabolism, a process in which lipids are oxidized to create energy.
The research was led by Prof. Tami Geiger, Prof. Gal Markel and Dr. Michal Harel of TAU’s Sackler School of Medicine and Sheba’s Ella Lemelbaum Institute for Immuno-Oncology,
“In recent years, a variety of cancer immunotherapy therapies have been used, therapies that strengthen the anti-cancer activity of the immune system,” explained Markel, a senior oncologist and scientific director of the Ella Lemelbaum Institute at Sheba. “These treatments have been shown to be highly effective for some patients and have revolutionized oncology. However, many patients do not respond to immunotherapy, and it is critical to understand why.”
This knowledge will help predict who will respond to therapy and perhaps help alter treatment to increase response rates, he said. “In our research, we focused on metastatic melanoma, a devastating disease that until recently had no efficient treatments.”
Some 60% of patients with metastatic melanoma don’t react to these treatments, the researchers said. They set out to discover why.
In their work, they used a new approach called “protein mapping,” or so-called proteomics, using a mass spectrometer, an analytical tool that enables the mapping of thousands of proteins.
Using this protein mapping technology, they examined responses of 116 melanoma patients to immunotherapy. They found that there were differences in the metabolism, or energy production process, of the cancer cells between those patients for whom immunotherapy was successful and those for whom it was not.
The tumors of patients who responded well to immunotherapies had a higher fatty acid metabolism, said Prof. Geiger in a phone interview.
In collaboration with the Salk Institute in San Diego and Yale School of Medicine, the researchers then examined their findings in melanoma tissue cultures and a mouse model of metastatic melanoma.
Using genetic engineering, they were able to “silence” the mechanism responsible for fatty acid metabolism, causing the levels to drop.
When the fatty acid metabolism is lower, said Geiger, “the cancer cells manage to ‘hide’ from T-cells that are supposed to detect and destroy them. As a result, cancer in these mice developed at a faster rate compared to the control group.” T-cells play a central role in the immune response.
The findings can lead to two main developments, Geiger explained. The levels of fatty acid metabolism could be checked in melanoma patients, and those who have high levels should take the immunotherapy track, knowing that success rates will be higher. Those who don’t will know in advance that the treatment won’t help.
In these cases, however, she said, it may be possible to raise the levels of fatty acid metabolism in the cancer cells with medication, to make them and the patients more receptive to immunotherapies, she said.
The researchers are now looking into that option with a follow-up study, she said. The findings may also be helpful for patients with other malignancies, she added.
“Now, in subsequent studies, we are looking for ways to improve the response to immunotherapy and expand the circle of patients who benefit from it,” said Markel. “In addition, we are looking for a method that will allow clinicians to anticipate which patients will respond to treatments.”
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