Transgenic T cell Immunotherapy Targeting Prostate-Restricted Epithelial Antigens in Prostate Cancer
Abstract
Prostate cancer is a leading cause of death in men in the United States, and it is estimated that one in seven men will be diagnosed with prostate cancer during their lifetime. If caught early enough, most prostate cancers can be cured with local therapies such as chemotherapy and radiation. Most prostate tumors that do not respond to local therapies are also sensitive to hormones, such as androgens, and androgen deprivation therapy often slows down tumor growth and increases life expectancy in men receiving these treatments. Unfortunately, resistance to hormone-based therapies is inevitable in these men, and they ultimately develop castration-resistant prostate cancer, which has a poor prognosis and no effective treatment options. The use of immunotherapies designed to redirect an individual’s immune system to kill cancer cells has become a popular strategy in the cancer field. Adoptive T cell therapies are a common form of immunotherapy. T cells can kill other cells in the body based on their ability to recognize small pieces of specific proteins, known as peptide antigens, on the surface of those cells based on an individual’s human leukocyte antigen type (HLA). They most commonly recognize peptide antigens from pathogens such as viruses to kill infected cells and prevent disease. For adoptive T cell therapies against cancer, we remove a cancer patient’s blood, identify T cells that recognize peptide antigens on their cancer cells, generate a large population of the cancer-specific T cells, and put them back into the cancer patient to kill their cancer cells. However, it has been difficult to identify prostate cancer-specific proteins that are not expressed in healthy tissues, which has made the development of transgenic T cell therapies challenging. By studying all the genes and proteins expressed in prostate epithelial cells, we have identified multiple proteins expressed in large amounts in normal as well as cancerous prostate tissue, known as prostate-restricted epithelial antigens (PREAs). Although these proteins are expressed in normal prostate tissue, we believe they will serve as good prostate cancer signals for T cells to target because the prostate is not an essential organ and, in most advanced cases of prostate cancer, the prostate has been removed or irradiated. These proteins also have limited expression in other essential organs in the body. We propose to use a combination of new and efficient approaches to identify peptide antigens from PREAs from common HLA types and to engineer transgenic T cells targeting prostate cancer for potential use as an adoptive clinical therapy for castration-resistant prostate adenocarcinoma patients. We would like to complete the studies identifying and characterizing PREAs within 6 months. We will then identify the T cell receptors that recognize each antigen and engineer T cells expressing specific T cell receptors to target and kill cells expressing PREAs. Finally, the engineered T cells will be thoroughly tested for their ability to eliminate the growth of prostate cancer cells grown in culture dishes or in animals as tumors. If the T cells successfully prevent tumor cell growth in these laboratory studies, we will pursue their use for adoptive therapy in clinical trials to assess their effects in men with castration-resistant prostate cancer. My primary career goal is to become an independent investigator at the forefront of prostate cancer research to improve the quality of life and clinical outcome of men with prostate cancer by developing safer, more effective immunotherapies for advanced prostate cancer. This project exposes me to the full process of identifying, engineering, optimizing, and applying a T cell therapy against cancer. I will receive formal training in next-generation sequencing technologies and computational biology. I will also attend numerous meetings, seminars, and conferences at Fred Hutchinson Cancer Research Center and na
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010119
Entities
People
- Diana C. DeLucia
Organizations
- Fred Hutchinson Cancer Center
- United States Army