Why Immunotherapy fails 60% of Metastatic Melanoma Patients

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Why Immunotherapy fails 60% of Metastatic Melanoma Patients

Brian Blum — Israel21c
Sep 29, 2019

The ultimate goal is to improve personalized medicine. "Can we predict who will respond?" asks Markel. "Can we alter treatment in order to increase responses?"

Immunotherapy has transformed the treatment of many cancers, turning them from incurable to manageable as a kind of chronic illness.

But not metastatic melanoma. More than half of patients (some 60 percent) with the disease do not respond to immunotherapy treatments.

Researchers at Tel Aviv University's Sackler School of Medicine and Sheba Medical Center's Ella Lemelbaum Institute for Immuno-Oncology wanted to know why.

The researchers reviewed the results of 116 melanoma patients treated with immunotherapy. Using a protein mapping technique called proteomics, the researchers discovered a difference in the metabolism, or energy production process, between melanoma patients for whom immunotherapy worked, and those whose cancer proved resistant.

Prof. Tami Geiger, head of the Proteomics Lab at Tel Aviv University, explained that her team was able to map thousands of proteins using a mass spectrometer.

"We then followed up with extensive computational analysis to identify the proteins that differentiated between the response groups," Geiger said.

The main distinction, according to Geiger: "In the responders, we found higher levels of proteins associated with lipid metabolism, which led to better recognition by the immune system."

Lipids are the building-block molecules of living cells; they are oxidized to create energy in the body in a process known as fatty acid metabolism.

Patients whose cancer cells had a faster fatty acid metabolism responded to immunotherapy, while cancer cells that had a slower fatty acid metabolism were able to "hide" from the immune system's T-cells that are supposed to destroy them.

The research was done on mice in collaboration with the Salk Institute in San Diego and Yale School of Medicine. Using genetic engineering, the researchers "silenced" the mechanism responsible for fatty acid metabolism. "Cancer in these mice developed at a faster rate compared to the control group," Geiger said.

Predicting Who Will Respond Best

The results could be significant – and not just for melanoma.

"These findings can also be relevant to many other malignancies," said Sheba Medical Center's Prof. Gal Markel, who led the study with Geiger and Dr. Michal Harel.

The ultimate goal is to improve personalized medicine. "Can we predict who will respond?" asks Markel. "Can we alter treatment in order to increase responses?"

For the moment, the research will only indicate which patients should take the immunotherapy track and which patients should not because they will know in advance that treatment won't help.

In the future, if scientists can develop targeted medication to raise the levels of fatty acid metabolism, that may help make the 40% of unresponsive patients more receptive to immunotherapies.

"In subsequent studies, we [will be] looking for ways to improve the response to immunotherapy and expand the circle of patients who benefit from it," said Markel.

Melanoma is the most dangerous type of skin cancer. Although it accounts for only about one percent of skin cancers, it causes a large percentage of skin cancer deaths, according to the American Cancer Society.

Some 7,230 people are expected to die of melanoma in the United States this year. Melanoma is called metastatic when the cancer has spread to other parts of the body.

The results of the Tel Aviv team's research were published in the September issue of the medical journal Cell.

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