A potential new way to fight melanoma by blocking one of the immune system's checks and balances was reported in a recent issue of JCI Insight by researchers at the University of North Carolina Lineberger Comprehensive Cancer Center.
The team is developing a potential new immunotherapy strategy for melanoma based on their insights into Autoimmune Polyendocrinopathy Type 1, a rare, inherited disorder in which T cells attack healthy cells and tissues.
People who have a mutation in the Autoimmune Regulator, or Aire, gene cannot destroy T cells that are "self-reactive. " Therefore, these self-reactive T cells survive destruction within the thymus, the central immune organ in which T-cells mature, and attack healthy cells and tissues, including melanocytes.
"The majority of T cells will go and fight off bad things like fungus, bacteria and viruses," the study's senior author Maureen Su, M.D., UNC Lineberger member and associate professor in the UNC School of Medicine Division of Pediatric Endocrinology. said. "But a small percentage of these T cells, by chance, can recognize cells that are 'self.' The people who are missing a functional Aire gene lack the ability to delete self-reactive T cells. But what we realized is that while they're prone to auto-immune disease, they're probably pretty good at fighting off cancer, too."
In an effort to block Aire and prevent the immune system from killing off T cells that might recognize melanoma, researchers tested a compound, an anti-RANKL antibody in mice. They studied the effects of this treatment in combination with ipilimumab, an FDA-approved immunotherapy. Ipilimumab works by releasing the brakes on T-cells so they can attack tumors. However, not all patients respond to these drugs. Researchers believe that along with their Aire-blocking compound, they can allow more T cells to survive so they can go on to attack melanoma.
They determined that ipilimumab improved survival in mice that had a genetic mutation that caused a partial loss of Aire. In addition, combining the anti-RANKL antibody with ipilimumab produced a synergistic effect and helped prolong survival.
To investigate if blocking Aire has a synergistic effect with ipilimumab in humans, researchers drew from a study of people who have natural genetic variations for the Aire gene that are known to make the Aire protein unstable and therefore short-lived in normal cells. A study of six people with these variations, out of 79 patients who were previously treated with ipilimumab for metastatic melanoma, found a higher likelihood of progression-free survival. However, because the incidence of these naturally occurring polymorphisms is less than 10% in the overall, researchers believe using the anti-RANKL antibody could allow them to produce this same effect in more patients.