Ipilimumab (anti-CTLA-4 IgG1) treatment is the first FDA-approved therapy to confer survival benefit in metastatic melanoma. Two important limitations to this therapy, however, are that 1) 10-15% of patients develop serious or life-threatening immune-related adverse events (IRAEs) that resemble autoimmune disease, and 2) only 10-20% of patients demonstrate a therapeutic response. Genetic determinants of IRAE predisposition and therapeutic response are currently unknown, and whether the same genetic determinants predispose to both IRAE development and melanoma regression is also unclear. Identifying biomarker(s) that predict outcome could allow preventive treatment for life-threatening autoimmunity and focusing of resources on patients who are most likely to benefit. The Autoimmune regulator (Aire) gene has a well-described role in organ-specific immune tolerance. How Aire deficiency impinges on therapeutic response and autoimmune side effects during CTLA-4 blockade, however, is currently unknown. We hypothesize that variation in Aire function is a major determinant of both therapeutic response and autoimmune side effects during CTLA-4 blockade. In Aim 1, we will determine the combinatorial effects of Aire deficiency and anti-CTLA-4 antibody therapy on the development of autoimmunity. In Aim 2, we will determine how changes in Aire function may influence therapeutic response to anti-CTLA-4 antibody treatment in melanoma.
PI: Maureen Su, MD
Department: Pediatrics, Microbiology & Immunology