Aging metabolism reduces effectiveness of CAR-T cell therapy

A Ludwig Cancer Research study has discovered that the metabolic decline that accompanies aging impairs the efficacy of CAR-T cell therapy, an immunotherapy in which T cells of the immune system are taken from patients, engineered to target cancer cells and reinfused into the same patients for treatment.

Researchers led by Ludwig Lausanne's Helen Carrasco Hope and Nicola Vannini, and their colleague Denis Migliorini of Geneva University Hospitals, report in the current issue of Nature Cancer how dysfunctional mitochondria-which are essentially the batteries of the cell-compromise the ability of CAR-T cells derived from aged mice to kill cancer cells. This dysfunction, they show, stems from the age-related decline in pools of NAD+ (nicotinamide adenine dinucleotide), a molecule of critical importance to energy production, metabolism and mitochondrial function. The researchers report that replenishing NAD+ reverses this dysfunction in preclinical models of cancer, suggesting a novel strategy to enhance cell therapies for older cancer patients.

Our findings strengthen the growing recognition that aging fundamentally reshapes immune cell function and metabolism. 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 mind-where most patients are older adults."

Helen Carrasco Hope, Ludwig Lausanne

The researchers show that CAR-T cells produced from the T cells of aged mice tend to lack "stemness"-the capacity to expand rapidly and efficiently kill their cellular targets. These capabilities are restored by NAD+ supplementation. To do that, the team used NAD+-boosting compounds currently under clinical investigation for other conditions, demonstrating that their strategy may be readily translated for clinical evaluation as a support for CAR-T cell cancer therapies.

Notably, parallel analyses of clinical datasets by the researchers confirmed that both chronological age and NAD⁺-related gene expression correlate with outcomes of CAR-T therapy in patients.

"This is a major step toward personalized and age-conscious immunotherapy," said Vannini. "By correcting age-related metabolic defects, we could improve outcomes for a large segment of cancer patients."