Age is a negative predictor of CAR-T therapy efficacy according to the research linked below. Because myeloma is a cancer mainly in older people (the average age of newly diagnosed MM patients is 70), MM survivors must take their age and the strength of their immune system into account when considering CAR-T cell therapy.
While the study below doesn’t discuss it in so many words, “t-cell quality” and “host immune environment” both point to how much toxicity the MM patient has had going into CAR-T therapy. Meaning, if the MM patient has had a lot of chemo, they may have low t-cell quality and their immune environment may be lacking?
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…
Several investigations have reported that aging leads to deficient immune and metabolic functions that result in altered antitumor responses25. Interestingly, mitochondrial dysfunction is a hallmark of aging26 and NAD decline has been described across several tissues, including white adipose tissue (WAT), muscle and liver27,28,29—
Restoration of NAD levels rescues functionality of aged CAR-T cells
In conclusion, our study found that aging is an important limiting factor for CAR-T cell therapy. Specifically, aged T cells present reduced NAD cellular levels that are linked to decreased mitochondrial fitness, ultimately preventing the maintenance of stem-like properties of CAR-T cells and leading to deficient long-term survival in vivo and tumor growth control.
These findings emphasize the importance of using aged models in the field of cancer immunology, which can uncover mechanisms of CAR-T cell failure that are often overlooked in preclinical studies, shedding light on novel strategies that can ameliorate CAR-T cell therapy.”
age myeloma CAR-T age myeloma CAR-T age myeloma CAR-T
