Development of Next-Generation STEAP1 Chimeric Antigen Receptor T-Cell Therapies to Combat Antigen Escape and T-Cell Dysfunction
Abstract
Prostate cancer is the second most common cause of cancer-related death in men in the United States. It relies on sex hormones called androgens for survival and growth, and drugs blocking these hormones are the first line of treatment for advanced prostate cancer. However, prostate cancers eventually become resistant to these drugs. When the cancer spreads to the bones, distant lymph nodes, and other organs, it is known as metastatic disease and is incurable. A patient’s immune T cells can be genetically engineered to carry chimeric antigen receptors (CAR) that recognize cancer-specific proteins and then kill the cancer cells that display those proteins. CAR-T cell therapies have shown great efficacy against blood cancers, but have been less successful against prostate cancer and other solid tumors. Aiming to successfully treat metastatic prostate cancers, we developed a CAR-T cell therapy targeting the STEAP1 protein that is found on most prostate cancers. It has shown excellent activity against prostate cancer in laboratory models. However, mice treated with the CAR-T cells eventually relapse due to decreased STEAP1 protein in the cancer or loss of anti-cancer CAR-T cell activity. I now propose to address these issues that prevent the cure of prostate cancer with STEAP1 CAR-T cell therapy. Regarding the loss of STEAP1 protein, I will design and test a CAR-T cell therapy that simultaneously targets two proteins on prostate cancer: STEAP1 and another known as PSMA, which are both expressed at high levels in the same cancer cells. To address the loss of CAR-T cell anti-cancer activity, I will investigate next-generation STEAP1-specific CAR-T cells that are less likely to become fatigued and more likely to continue attacking cancer. The results of these studies will advance novel CAR-T cell therapies that can halt prostate cancer progression and reduce patient mortality while also informing CAR-T cell therapy advances against other solid tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310089
Entities
People
- Vipul Bhatia
Organizations
- Fred Hutchinson Cancer Center
- United States Army