Metastatic Melanoma Patients Are Not Respond To Immunotherapy

Tel Aviv University and Sheba Medical Center researchers say they have discover why more than half of patients with metastatic melanoma do not respond to immunotherapy cancer treatments. Wielding proteomics, an innovative “protein mapping” approach, a team of researchers 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 have answered the burning question.

The researchers, whose findings were published on September 5 in Cell; compare the responses of 116 melanoma patients to immunotherapy—one group in which immunotherapy was successful and a second in which immunotherapy was not successful. Harnessing proteomics, a powerful protein mapping technology; they discovered differences in the metabolism; or energy production process; of the cancer cells of the two groups.

Cancer immunotherapy therapies

“In recent years, a variety of cancer immunotherapy therapies have use; therapies that strengthen the anti cancer activity of the immune system,” explains Prof. Markel, a senior oncologist and scientific director of the Ella Lemelbaum Institute. “These treatments have been shown to be highly effective for some patients and have revolutionized oncology. However, many patients do not respond to immunotherapy; also it is critical to understand why.

“Can we predict who will respond? Can they alter treatment in order to increase responses? In our research; they focus on metastatic melanoma; a devastating disease that until recently had no efficient treatments. It was clear to us that pre-treatment samples from responders and non-responders would be key.” To better understand treatment resistance mechanisms; the scientists examine tumors take from 116 patients using proteomics.

So in the proteomic lab, they use an instrument called a mass spectrometer; which enables global mapping of thousands of proteins, explains Prof. Geiger, head of TAU’s Proteomics Lab. They then follow up with extensive computational analysis to identify the proteins that differentiated between the response groups. The proteomic comparison identify major differences between responders and non-responders to immunotherapy.

Proteins with lipid metabolism

So in the responders, they found higher levels of proteins with lipid metabolism; which led to better recognition by the immune system,” says Prof. Geiger. In collaboration with the Salk Institute in San Diego and Yale School of Medicine; researchers then examined their findings in melanoma tissue cultures and a mouse model of metastatic melanoma. So using genetic engineering; they were able to silence the mechanism responsible for fatty acid metabolism.

So they find that upon silencing this metabolic pathway; the cancer cells manage to ‘hide’ from T cells that are supposed to detect and destroy them, says Prof. Geiger. As a result, cancer in these mice developed at a faster rate compare to the control group. In our study, we identified a significant difference between melanoma patients who live for years thanks to immunotherapy; also patients who are not at all affected by the treatment.

“These findings can also be relevant to many other malignancies,” adds Prof. Markel. “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. So in addition, they are looking for a method that will allow clinicians to anticipate which patients will respond to treatments.”