Mohamed Mahameed, PhD
Project Title
Stress-Adaptive Control of CAR Expression to Prevent CAR-T Cell Exhaustion
About the Investigator
Dr. Mohamed Mahameed’s research focuses on the intersection of cancer and synthetic biology, with the goal of developing novel cell-based therapies. Dr. Mahameed received his BSc in Pharmacy, MSc in Medicinal Chemistry, and PhD in Pharmacology from the Hebrew University of Jerusalem. Dr. Mahameed then completed postdoctoral training at ETH Zurich, Switzerland, where he specialized in mammalian synthetic biology for therapeutic applications. In 2024, he returned to the Hebrew University of Jerusalem, where he is currently an Assistant Professor at the Institute for Drug Research.
About the Research
Chimeric antigen receptor (CAR) T-cell therapy is a powerful cancer treatment that uses a patient’s own immune cells to recognize and kill cancer cells. While this approach has shown remarkable success in blood cancers, its effectiveness is often limited by a major problem: CAR-T cells can become “exhausted,” meaning they lose their ability to function over time. This problem is especially severe in solid tumors, where CAR-T therapy has had limited success.
This project is based on the idea that continuous activity of the CAR receptor places a heavy burden on the cell’s internal protein-handling machinery, causing cellular stress. In response, cells activate a stress-management pathway known as the unfolded protein response (UPR). While this response is helpful in the short term, prolonged activation can damage T-cell function and drive exhaustion.
The goals of this research are threefold. First, we will determine how cellular stress and UPR signaling contribute to CAR-T cell exhaustion in living cancer models. Second, we will engineer a novel “stress-regulated” genetic switch that allows CAR-T cells to temporarily reduce CAR expression when stress levels are high, protecting them from exhaustion. Third, we will test whether this strategy improves CAR-T cell performance in solid tumors, where stress levels are particularly high.
By enabling CAR-T cells to dynamically adapt to stressful tumor environments, this work aims to create more durable and effective cancer immunotherapies. Ultimately, this approach could help extend the benefits of
CAR-T therapy to patients with solid tumors and improve long-term treatment outcomes.
