Swiss researchers have uncovered a critical link between aging and the diminished effectiveness of CAR-T cell therapy, one of the most advanced forms of cancer immunotherapy. The collaborative study, conducted by teams from the University of Lausanne (UNIL), Lausanne University Hospital (CHUV), Geneva University Hospitals (HUG), and the Ecole Polytechnique Fédérale de Lausanne (EPFL), reveals how age-related metabolic changes compromise the therapeutic potential of engineered immune cells.
CAR-T therapy involves extracting a patient's T cells, genetically modifying them to recognize and attack cancer cells, and then reinfusing them into the patient. While this approach has shown remarkable success in certain cancers, its efficacy in older patients has been less consistent.
Age-Related Metabolic Decline Affects CAR-T Function
The research team found that CAR-T cells derived from aged mice exhibited significant functional impairments compared to those from younger subjects. These aged cells demonstrated poor mitochondrial function, reduced "stemness" (the ability to self-renew and differentiate), and markedly decreased antitumor activity.
At the molecular level, researchers identified a substantial drop in nicotinamide adenine dinucleotide (NAD) levels as the primary culprit. NAD is a crucial molecule that plays a central role in cellular energy production and mitochondrial metabolism.
"CAR-T cells from older individuals are metabolically impaired and significantly less effective," explained Dr. Helen Carrasco Hope, one of the study's researchers. "What's exciting is that we were able to rejuvenate these aged cells by restoring their NAD levels — reviving their antitumor function in preclinical models."
Implications for Cancer Treatment in Aging Populations
This discovery has significant implications for cancer treatment, particularly as most cancer patients are older adults. The immune system naturally deteriorates with age, a process known as immunosenescence, which can make immunotherapies less effective precisely in the population that needs them most.
The findings highlight a critical gap in current preclinical research models, which often fail to account for age-related factors when developing new therapies.
"Our findings strengthen the growing recognition that aging fundamentally reshapes immune cell function and metabolism," Dr. Hope noted. "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."
Potential for Metabolic Intervention
The most promising aspect of the study is the demonstration that age-related CAR-T cell impairment may be reversible. By restoring NAD levels in aged CAR-T cells, researchers were able to rejuvenate their antitumor function in laboratory models.
This suggests that metabolic interventions targeting NAD pathways could potentially enhance the efficacy of CAR-T therapy in older cancer patients. Such approaches might include NAD precursor supplementation or other strategies to boost cellular metabolism.
The research represents an important step toward developing more effective cancer immunotherapies for aging populations and underscores the importance of considering age-related factors in cancer treatment development. As the global population continues to age, addressing these age-specific challenges in cancer therapy becomes increasingly critical for improving patient outcomes.
