T Cell Dysfunction in TSC: Mechanisms and Targeted Therapy
Abstract
Tuberous sclerosis complex (TSC) is a multi-system disorder in which benign tumors of the brain, skin, kidney, and heart can develop. Blood-vessel filled tumors called angiomyolipomas occur in the majority of children and adults with TSC. Currently, angiomyolipomas can be treated with inhibitors of the mammalian target of rapamycin (mTOR). These inhibitors only partially decrease angiomyolipoma size and the angiomyolipomas regrow when treatment is stopped. Therefore, continuous and lifelong treatment is required, with accompanying side effects, which can include mouth sores, high lipid levels, irritation of the lungs (interstitial pneumonitis), and delays in puberty, especially in girls. This project is focused on using the body s own immune system to treat angiomyolipomas, referred to as "immunotherapy" with the goal of eliminating these tumors. If successful, this would represent a major breakthrough. White blood cells (WBCs) are cells of our immune system that are involved in protecting the body against foreign invaders and eliminating abnormal cells including tumor cells. However, WBCs within tumors are often prevented from recognizing and destroying tumor cells. This occurs in part because specific proteins (CTLA-4 and PD-1) put "brakes" on the surface of "killer T cells" (a specialized type of WBC that kills tumor cells). In dramatic breakthroughs in the past 5 years, it has been discovered that releasing the "brakes" on killer T cells by using monoclonal antibodies (a type of immunotherapy) can restore the natural tumor-fighting ability of killer T cells. This can lead to long-lasting clinical results in melanoma, kidney cancer, and certain types of lung cancer. Immunotherapy was named the "Top Breakthrough" in 2013 by Science magazine and monoclonal antibodies made against PD-1 and CTLA-4 received accelerated approval by the US Food and Drug Administration (FDA) in March 2011 and September 2014, respectively. Our long-term goal is to use these powerful tools to treat and eliminate tumors in TSC, including angiomyolipomas. Our preliminary data indicate that the killer T cells in TSC-deficient tumors exhibit classic signs of "brakes." We have also found evidence using mouse models that the immune system plays a pivotal role in the controlling growth of tumor cells in TSC. Our central hypothesis is that targeting the "brakes" on killer T cells in angiomyolipomas will restore the tumor-fight ability of killer T cells, allowing them to eliminate TSC-deficient tumor cells. This hypothesis will be addressed by determining why killer T cells have brakes on them in TSC tumors, investigating the impact of T cells on TSC tumor growth, and studying monoclonal antibody immunotherapies alone and in combination with Rapamycin in mouse models of TSC. Our long-term goal is to understand how T cells participate in the development of tumors in TSC and determine how immunotherapies can be used to improve the lives of children and adults with TSC. Given that these therapies are already FDA-approved, this concept has the potential to be fast-tracked to clinical trials in TSC. In conclusion, immune-mediated strategies represent a completely new approach for angiomyolipoma therapy, with the potential for a profound and even paradigm-shifting clinical impact.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710150
Entities
People
- Elizabeth P Henske
Organizations
- United States Army