Study Reveals How Aging of CAR-T Cells Contributes to Cancer Recurrence

Mayo Clinic researchers have uncovered a significant factor behind cancer relapse in patients treated with chimeric antigen receptor T-cell (CAR-T) therapy. Over time, these engineered immune cells undergo aging, known as senescence, which diminishes their ability to combat cancer effectively. The study, published in Molecular Cancer, identifies this aging process as a key mechanism of CAR-T failure, offering new insights into therapy resistance.

The team found that the way CAR-T cells are designed influences their longevity. Specifically, certain intracellular features, such as recognition and activation signals, can overwork the cells if too intense or prolonged. This excessive activation accelerates cellular aging, leading to reduced proliferation and tumor-killing capacity. They developed laboratory models to simulate long-term stress on CAR-T cells and observed that cells engineered with the 4-1BB signaling domain were more prone to senescence, while those with the CD28 domain showed better durability due to lower stress levels. Validation in patient samples confirmed these findings.

Understanding this process opens avenues to engineer CAR-T cells more resistant to aging, potentially enhancing their persistence and effectiveness. Dr. Ismail Can emphasized that comprehending early molecular triggers of senescence is crucial for designing longer-lasting therapies. This research paves the way for optimizing CAR-T cell design not only for blood cancers but also for solid tumors, aiming to reduce relapse rates and improve patient outcomes.

Dr. Saad Kenderian highlighted that this discovery is a vital step toward addressing the challenge of CAR-T therapy failure. By targeting the biological mechanisms underlying cell aging, future therapies could be more durable and applicable to a broader range of cancers.