NAD Deficiency Impairs CAR-T Cells Derived from Older Adults
Nicotinamide adenine dinucleotide (NAD) is involved in mitochondrial metabolism. Levels decline with age and there has been some interest in finding ways to increase NAD in mitochondria via various approaches, largely using supplements derived from niacin, such as nicotinamide riboside and nicotinamide mononucleotide. These do not appear to work all that well, based on the history of clinical trials conducted to date. Nonetheless, researchers here suggest low NAD is an important determinant of the relative lack of effectiveness of CAR-T therapies targeting cancer in older people. Chimeric antigen receptor (CAR) T cells are produced from T cells taken from the patient, engineered to add features that allow them to target the patient's cancer cells, expanded in culture, and returned to the patient. To the degree that the patient's T cells are less effective, CAR-T therapy is less effective.
Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy.
Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. We used the small molecule 78c to specifically block the NAD-degrading activity of CD38, and we combined it with nicotinamide mononucleotide (NMN) supplementation. We observed that, according to the previous data, NMN alone was not sufficient to increase NAD levels in aged T cells. However, when combined with the CD38 inhibitor 78c, NAD levels were restored to levels seen in younger controls. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.