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<p>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. 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月20日

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  • Helen Carrasco Hope,
  • Jana de Sostoa,
  • Pierpaolo Ginefra,
  • Massimo Andreatta,
  • Yi-Hsuan Chiang,
  • Catherine Ronet,
  • Christine Pich-Bavastro,
  • Jesús Corria Osorio,
  • François Kuonen,
  • Johan Auwerx,
  • Patrizia D’Amelio,
  • Ping-Chih Ho,
  • Santiago J. Carmona,
  • George Coukos,
  • Denis Migliorini,
  • Nicola Vannini

摘要

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. 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.