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2024 Estate of Joseph Bolus – PCF Young Investigator Award

Developing Engineered Immune Cell Therapies for Metastatic Castration-Resistant Prostate Cancer to Increase Efficacy and Decrease Toxicity

Nour Shobaki, PharmD, PhD
University of Pennsylvania

Mentors: Carl June, MD; Vivek Narayan, MD

Description:

  • Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive and often lethal stage of prostate cancer that typically spreads to the bones and resists standard therapies, including checkpoint immunotherapy. 
  • Chimeric antigen receptor (CAR) T cell therapy is a promising type of immunotherapy in which patients’ immune cells are engineered to find and kill cells that express a specific tumor-associated protein. However, there are not yet any approved CAR T cell therapies for solid tumors, including prostate cancer, largely due to safety concerns and limited efficacy. 
  • Dr. Nour Shobaki’s project will address the major challenges that limit the efficacy of CAR T cell therapy in mCRPC: reducing the harmful side effects when CAR T cells attack healthy tissues alongside cancerous ones; overcoming the ability of cancer cells to evade treatment by developing resistance to CAR T cells; and resisting the tumor harsh environment that weakens the body’s immune response.   
  • A novel multi-pronged CAR T cell approach will be developed. First, CAR T cells will be designed with high precision to help minimize the risk of unintended side effects. Second, these CAR T cells will be equipped to enhance their own activity and to boost the body’s own immune cells to attack resistant cancer cells. Lastly, these CAR T cells will be modified to resist the tumor’s immune barriers, increasing CAR T cell persistence and anti-tumor activity.  
  • The efficacy of this CAR T cell approach will be tested in physiologically relevant mouse models of human prostate cancer, and a safe therapeutic index will be established.  
  • If successful, this project will result in a new CAR T cell approach for advanced prostate cancer, that can overcome prior limitations including toxicity, the immunosuppressive tumor microenvironment, and tumor heterogeneity or loss of expression of the targeted protein.  

What this means to patients: CAR T cell therapy has been highly effective in various types of lymphoma and leukemia but has not yet been optimized for solid tumors like prostate cancer. Dr. Shobaki’s project uses a multi-pronged approach to overcome prior issues of safety and efficacy in prostate cancer by combining CAR T cells engineered with other strategies and modulation of the immunosuppressive tumor microenvironment. This will provide a foundation for the design of future clinical trials to provide safe and effective treatments for patients with mCRPC.