Rejuvenating TCR-T Cells to Treat and Prevent Relapse in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive, life-threatening blood cancer that remains very difficult to cure despite treatment advances. Each year approximately 20,000 people in the United States are diagnosed with AML, and cases are rising worldwide as the population ages. For many patients, the most effective therapy is a stem cell transplant, where healthy donor blood-forming cells replace the patient’s diseased bone marrow. Unfortunately, relapse after transplant is common, and survival rates in these cases remain below 20%. These challenges underscore the urgent need for new therapies that provide more durable and lasting cures.

One promising strategy is adoptive cellular therapy, which involves engineering a patient’s own immune cells to better recognize and attack their cancer. T cells are immune cells that normally defend the body from infections and tumors. Early clinical studies have shown that reprogramming T cells to recognize the Wilms’ Tumor Antigen 1 leukemia marker can be done safely, but the benefits for patients have been modest. The main reason is that T cells quickly become dysfunctional once they encounter leukemia cells. Instead of multiplying and sustaining the attack, they lose energy, stop dividing, and disappear.

This project is designed to elucidate and overcome that barrier. In AML, T cells don’t just become “tired” as seen in other cancers, but instead enter a state of premature aging, known as senescence. In this state, they lose the signals that normally keep them active, begin to resemble other immune cell types, and stop expanding. By studying patient samples and laboratory models, we aim to identify the molecular switches that drive this senescent state. We will then test whether blocking the stress signals that enforce senescence can restore T cell health and persistence. Finally, we will explore ways to reintroduce the lost signals, helping engineered T cells survive longer and function more effectively.

Our ultimate goal is to design durable cellular therapies that can improve survival for patients with high-risk AML. If successful, this work will not only expand treatment options for leukemia patients who currently have few alternatives but also advance immunotherapy against cancers more broadly. By uncovering new ways to reverse immune dysfunction, these findings may help bring lasting, life-saving treatments to more people.