Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure

Area of Science:

• Immunology
• Gerontology
• Cancer Biology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise for cancer treatment.
• Hurdles exist that limit CAR T-cell therapy's application and efficacy.
• The impact of aging on CAR T-cell outcomes remains largely unknown.

Purpose of the Study:

• To investigate how aging influences CAR T-cell functionality.
• To explore the role of mitochondrial dysfunction and NAD metabolism in age-related CAR T-cell impairment.
• To assess strategies for improving CAR T-cell therapy in older individuals.

Main Methods:

• CAR T-cells were generated from aged and young female mice.
• Mitochondrial function and NAD levels were assessed in CAR T-cells.
• In vivo functionality of CAR T-cells was evaluated.
• Human data analysis correlated age and NAD metabolism with CAR T-cell therapy responsiveness.
• NAD pathways were targeted to restore CAR T-cell function.

Main Results:

• CAR T-cells from aged mice exhibited mitochondrial dysfunction linked to NAD depletion.
• Aging led to reduced stem-like properties and impaired in vivo functionality of CAR T-cells.
• Human data indicated that both age and NAD metabolism impact CAR T-cell therapy response.
• Targeting NAD pathways successfully restored mitochondrial fitness and function in CAR T-cells from older adults.

Conclusions:

• Aging is a significant limiting factor for successful CAR T-cell responses.
• NAD depletion contributes to age-related CAR T-cell dysfunction.
• Restoring NAD metabolism presents a promising strategy to enhance CAR T-cell therapy efficacy in aging populations.