Immunotherapy, specifically the use of drugs that prevent tumors from shutting off immune cells, is a common treatment for skin cancer. However, about 25% of melanoma patients go on to see their tumors progress following an initial period of improvement. Since melanoma is one of the more aggressive types of skin cancer, figuring out how tumor resistance to immunotherapy comes about has significant potential for improving treatments. Researchers from UCLA may have part of the answer.
The research specifically revolves around the use of the “anti-PD-1” antibody known by the brand name of Keytruda. Although the treatment has been a huge leap forward in treating advanced melanoma, some tumors develop resistance to the treatment. Of the 78 patients that UCLA treated with Keytruda that the researchers had access to, 42 had a noticeable response and of these 15 went on to see their diseases progress. Of these 15, only four met the requirements of the analysis. The tumors of these four patients were checked periodically, had their cell lines analyzed, and were monitored for genetic changes.
It was found that one of the melanomas managed to lose a gene called “B2M”, which resulted in the tumor being seen differently by the immune system. In other words, the loss of this gene made it easier for the tumor to hide from the immune system even with the immunotherapy keeping immune cells from being shut off.
Two of the tumors had mutations in the JAK1 and JAK2 genes, causing them to be “selectively deaf” to signals that were trying to make the cancer cells stop their growth. Even though the immune system was active and working, the tumor was ignoring its efforts.
The fourth tumor also showed signs of immunotherapy resistance, though the researchers weren’t able to work out the mechanism behind it.
Although the sample size is admittedly small, the findings do pose some use for future development of skin cancer treatments and research. Two potential forms of immunotherapy resistance have been identified and with this information, work can begin on devising melanoma treatments that can potentially counter the mutations’ effects. Cancer is a constant back-and-forth between treatment development and tumor response and these findings are one more salvo in the ongoing war.
Zaretsky, J., et. al., “Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma,” New England Journal of Medicine, 2016; 10.1056/NEJMoa1604958
Ribas, A., “UCLA study unlocks key mechanisms that determine acquired resistance to immunotherapy in advanced melanoma,” UCLA web site, July 13, 2016; http://www.cancer.ucla.edu/Home/Components/News/News/938/1631?backlist=%2fpatient-care%2funderstanding-cancer%2fcancer-types-101%2fcervical-cancer, last accessed July 15, 2016.