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Can T cells be unleashed to attack skin tumors?

UNC Health Care System News Oct 10, 2017

Maureen Su, MD, and colleagues report on a potential new way to fight melanoma by blocking one of the immune system’s checks and balances, thus freeing immune cells to attack tumors and kill cancer cells.

Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center are using what they know about a rare, inherited autoimmune disease to turn the body’s defenses against melanoma.

In the journal JCI Insight, researchers report on a potential new way to fight melanoma by blocking one of the immune system’s checks and balances. Combining their strategy with an existing immunotherapy treatment that works by releasing the “brakes” on immune cells, they found they could shrink melanoma tumors, and prolong survival in preclinical models for melanoma.

“We have immune cells called T-cells that are really good at killing off cancer cells, but there is an inhibition system in place to prevent autoimmunity,” said the study’s senior author Maureen Su, MD, UNC Lineberger member and associate professor in the departments of pediatrics and microbiology and immunology at the UNC School of Medicine. “We have found a way to get rid of their inhibition so they can fight off cancer cells.”

The researchers are 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 with this condition can develop vitiligo, a condition in which their T-cells attack and kill the color-producing skin cells known as melanocytes, causing patches of color loss in skin. Researchers asked: If melanoma cells are the descendants of melanocytes, can those T-cells that are normally blocked from attacking melanocytes be activated to kill melanoma?

People who have a mutation in the Autoimmune Regulator (Aire) gene cannot destroy T-cells that are “self-reactive.” Therefore, these “self-reactive” T cells survive destruction within an organ called 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,” Su 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, a U.S. Food and Drug Administration-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
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