Mayo Clinic researchers have discovered a key reason some cancer patients relapse after receiving chimeric antigen receptor T-cell therapy, or CAR-T cell therapy. Over time, the engineered immune cells age and lose their ability to fight cancer.
Published in Molecular Cancer, the study identifies this aging process, known as senescence, as a previously unrecognized mechanism of CAR-T failure.
The researchers also showed that senescence is influenced by how CAR-T cells are engineered. Certain intracellular features — such as how the cell is programmed to recognize cancer and how strongly it is activated — can overwork the cells. The researchers found that if the activation signal is too intense or prolonged, it can push CAR-T cells into premature aging.
The discovery may guide the development of next-generation CAR-T therapies that last longer and are more effective across a broader range of cancers.
“This is one of the most clinically relevant discoveries we’ve made because it doesn’t just explain the cause of relapse, it gives us a biological target to possibly prevent it,” says Saad Kenderian, M.B., Ch.B., a principal investigator and hematologist at Mayo Clinic.
CAR-T therapy reprograms a patient’s own immune cells to recognize and destroy cancer. It has led to long-term remission for patients, including some with aggressive or treatment-resistant diseases. But many patients eventually relapse, and the causes have remained poorly understood.
Modeling CAR-T cell stress over time
To investigate why CAR-T therapy can fail, the Mayo team developed a novel lab model that simulates long-term biological stress, offering a clearer view of how the engineered cells behave after infusion. Over time, some CAR-T cells lost their ability to multiply and attack cancer. They showed hallmark signs of senescence, including distinct genetic changes.
The researchers found that senescence occurred more often in CAR-T cells built with a signaling feature, known as 4-1BB, which affects how the cells respond to cancer. In comparison, cells designed with an alternative domain, called CD28, were less affected by aging. These cells activate more quickly and persist for a shorter time, reducing the cumulative stress that drives senescence. The results were confirmed in multiple laboratory models and validated in patient samples.
Engineering CAR-T cells for longevity
That discovery was driven in part by the work of Ismail Can, Ph.D., who helped lead the molecular analysis behind the finding.
“Efforts to develop a significantly more durable CAR-T cell therapy will likely fail without a full understanding of why CAR-T cells sometimes fail. This study represents a significant step toward understanding why CAR-T cells fail,” says Dr. Can, first author of the study and a senior research fellow at Mayo Clinic’s T Cell Engineering Laboratory. “By identifying the early molecular triggers of senescence, we can begin to refine CAR-T design to potentially improve long-term function and reduce relapse.”
The findings highlight a new direction for CAR-T research, with potential implications not only for blood cancers but also for expanding cell therapy into solid tumors.
The study builds on Dr. Kenderian’s broader efforts to identify resistance mechanisms and design more durable and personalized immunotherapies.
This work was supported in part by Mayo Clinic Comprehensive Cancer Center, the Eagles 5th District Cancer Telethon Funds for Cancer Research, the State of Minnesota, and benefactors Georgia and Michael Michelson. For a complete list of authors, disclosures and funding information, review the study.
