Therapeutic Targeting of the Immune Checkpoint Molecule B7-H3 in TSC
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”. 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 of specific proteins in tumor cells inhibit the ability of “killer T cells” (a specialized type of WBC that kills tumor cells) to eliminate tumor cells. In dramatic breakthroughs in the past 9 years, it has been discovered that the tumor-fighting ability of killer T cells can be restored by using antibody-based targeted therapies (a type of immunotherapy), and that the approach can eliminate tumor cells. Immunotherapy was named the “Top Breakthrough” in 2013 by the prestigious journal Science magazine, and many different immunotherapies have received accelerated approval by the U.S. Food and Drug Administration (FDA) to treat over 20 cancer types today. My long-term goal is to use these powerful tools to treat and eliminate tumors in TSC, including angiomyolipomas. My preliminary data indicate that a protein related to PD-L1, named B7-H3, can suppress killer T cells in TSC. I have also found evidence using mouse models that inhibiting B7-H3 can significantly control the growth of tumor cells in TSC. My central hypothesis is that targeting the B7-H3 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 investigating the impact of B7-H3 on white blood cells in TSC (including killer T cells), and studying B7-H3 monoclonal antibody immunotherapy alone and in combination with either the mTORC1 inhibitor rapamycin or anti-PD-1 immunotherapy, which is approved for many types of cancer and has shown promising results in mouse models of TSC. My long-term goal is to understand how B7-H3 participates in the progression of tumors in TSC and determine how B7-H3 immunotherapies can be used to improve the lives of children and adults with TSC. Monoclonal antibodies against B7-H3 have already been used for human clinical trials, with no dose-limiting toxicities. The potential risks of anti-B7-H3 antibody in TSC, therefore, appear to be less than other immune-focused therapies. At least 12 B7-H3 targeted cancer clinical trials are currently ongoing (ClinicalTrials.gov). Thus, if our hypotheses are correct, there is a potential for rapid clinical trials and early benefits for TSC patients. In conclusion, immune-mediated strategies represent a completely new approach for TSC, with the potential for a profound and even paradigm-shifting clinical impact.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110223
Entities
People
- Heng-Jia Liu
Organizations
- United States Army