Ageing reduces CAR-T cell effectiveness by impairing metabolism, study shows

Lausanne [Switzerland], May 20 : People's immune systems deteriorate as they age, making cancer therapies that rely on immune cells difficult to implement.

In a new study, researchers from the University of Lausanne (UNIL), the Lausanne University Hospital (CHUV), the Geneva University Hospitals (HUG), and the Ecole Polytechnique Federale de Lausanne (EPFL) show that age-related immune decline has a measurable impact on CAR-T cell therapy, one of the most advanced forms of cancer immunotherapy.

CAR-T therapy works by engineering a patient's T-cells to recognize and destroy cancer cells. But the study found that CAR-T cells from aged mice had poor mitochondrial function, lower "stemness", and reduced antitumor activity. The culprit: a drop in levels of nicotinamide adenine dinucleotide (NAD), a molecule essential for cellular energy and metabolism of mitochondria.

"CAR-T cells from older individuals are metabolically impaired and significantly less effective," said first author Dr. Helen Carrasco Hope. "What's exciting is that we were able to rejuvenate these aged cells by restoring their NAD levelsreviving their antitumor function in preclinical models."

"Our findings strengthen the growing recognition that aging fundamentally reshapes immune cell function and metabolism," she added. "They highlight the urgent need to model age more accurately in preclinical studies, so that therapies are developed with the real-world cancer population in mindwhere most patients are older adults."

The team used NAD-boosting compounds currently under clinical investigation for other conditions, demonstrating that this approach is translatable and potentially applicable in humans. "This is a major step toward personalized and age-conscious immunotherapy," said senior author Dr. Nicola Vannini. "By correcting age-related metabolic defects, we could improve outcomes for a large segment of cancer patients."

The study adds to a growing body of work showing that age is not just a chronological number, but a biological factor that can shape therapy response. The authors call for age to be systematically considered in the development and evaluation of cell-based immunotherapies.

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