Interrogating the Safety and Efficacy of a Novel STEAP1 Chimeric Antigen Receptor T-Cell Therapy in Prostate Cancer
Abstract
Prostate cancer is a leading cause of cancer death in men in the United States. New treatment strategies are needed to disrupt the lethal progression of advanced prostate cancer. Therapeutic approaches that harness and redirect the body’s immune system to fight cancer have recently transformed the field of cancer medicine. These treatments are broadly referred to as immunotherapy. One type of immunotherapy is called chimeric antigen receptor (CAR) T cell therapy, where T immune cells can be purified from patients’ blood, engineered with a receptor designed to seek and destroy cancer, expanded in the laboratory, and re-infused into patients as a living drug. CAR T cells are highly selective and endowed with cancer killing abilities that far exceed those of existing chemotherapies. CAR T cell therapies have had amazing initial successes where they have cured advanced leukemias and lymphomas that were previously incurable. Exciting hints from early phase clinical trials indicate that CAR T cell therapy may soon be making headway in the treatment of solid tumors like prostate cancer. Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a protein found on the surface of >80% of prostate cancers and is not expressed at high levels in normal organs. This pattern of expression suggests that STEAP1 could be safely targeted with CAR T cell therapy to treat prostate cancer. For the past 2 years, our laboratory has focused on engineering a STEAP1 CAR T cell therapy from the ground up. We have successfully engineered a STEAP1 CAR T cell therapy candidate that specifically recognizes STEAP1 on human prostate cancer cells and kills them both in a culture dish and as tumors in mice without immune systems. However, these are simplified models that do not capture STEAP1 expression in normal human tissues and the suppressive immune landscape of prostate cancer that makes it resistant to many immunotherapies. These critical features are necessary to truly determine the safety and efficacy of our candidate STEAP1 CAR T cell therapy before clinical studies in men. Our current proposal therefore focuses on examining STEAP1 CAR T cell therapy in a recently developed human STEAP1 knock-in mouse model (called hSTEAP1-KI) with an intact immune system that was designed specifically to overcome these deficiencies and raise the bar. We will first establish the toxicities and anti-cancer effects of STEAP1 CAR T cell therapy in hSTEAP1-KI mice bearing prostate cancers that are hostile to immunotherapy like the human disease. We will then combine STEAP1 CAR T cell therapy with innovative approaches to (1) enhance antitumor responses by converting prostate cancer from a hostile and cold to a welcoming and hot environment for cancer-fighting immune cells including CAR T cells and (2) directly empower CAR T cells through genetic rewiring to remain active in the fight. Last, we will examine the effects of androgen and androgen receptor-targeted therapies (which are commonly used in men with advanced prostate cancer) on the production of STEAP1 CAR T cells and their anti-cancer activity. These studies will provide guidance on the basic but important question of whether concurrent castration or anti-androgen receptor therapy may boost or diminish the function of CAR T cells. Our proposed studies exceed the standard in the field by laying out an approach to rigorously characterize the safety and efficacy of our STEAP1 CAR T cell therapy in relevant mouse models early in development. We believe that this will enable optimization of STEAP1 CAR T cell therapy and combination treatment strategies well before testing in non-human primates and in humans. This is especially important because of the substantial cost, risk of injury and even death, or lack of antitumor responses associated with CAR T cell therapies that have not been fully vetted in the laboratory prior to clinical trials. Our goal is to advance STEAP1 CAR T cell th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110581
Entities
People
- John K Lee
Organizations
- Fred Hutchinson Cancer Center
- United States Army