CAR T cells target senescent cells, improve healthspan in mice

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Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of blood cancers in recent years. And there are positive signs that “living medicine” could be used against other diseases, such as autoimmune disorders.

Now laboratory research led by Memorial Sloan Kettering Cancer Center (MSK) and Cold Spring Harbor Laboratory suggests that these engineered immune cells hold promise for treating some diseases of aging, as well as -; Specifically, it is caused by the accumulation of senescent cells (senescent cells that stop dividing due to age or damage).

An infusion of CAR T cells designed to target senescent cells was not only able to improve metabolic function in older mice and premature mice fed a high-fat diet, but a single dose given to young, healthy mice also helped prevent metabolic decline later in life, the research team found. Published as per results Nature is aging.

When you hear ‘CAR T cell therapy’, you think ‘cancer’ -; And it’s understandable that it was pioneered in a place like MSK. But what we’re learning is that engineering approaches to immune cells to target disease has much broader potential.”


Scott Lowe, PhD, senior study author, chair of the Sloan Kettering Institute’s Cancer Biology and Genetics Program, MSc.

CAR T treatment improves metabolic function in mice

In the study, young mice were fed a high-fat diet for two months, which made them obese and caused metabolic stress. After infusion of experimental CAR T cells, mice had lower body weight, better blood glucose levels, and improved glucose and insulin tolerance despite continuing to eat a high-fat diet. They had fewer senescent cells in their pancreas, liver and fatty tissue than mice in a control group. Similar results were observed in aged mice where metabolic function decreased due to natural aging.

Aged mice that received the treatment took longer to tire during exercise. And the procedure did not cause any significant side effects.

More research is needed to see if this method can improve the “healthiness” of mice as well as increase their lifespan -; That is, how long they stay healthy and disease-free, scientists note.

“We continue to learn new things about aging at the biological level,” Dr. Lowe said. “It will take time, but we are eager to work with industry partners to transfer laboratory findings into clinical trials.”

There are several diseases associated with aging and chronic inflammation that can potentially be helped, Dr. Such as chronic obstructive pulmonary disease (COPD), nonalcoholic steatohepatitis (NASH), osteoarthritis, metabolic syndrome and even certain neurodegenerative diseases, says Low.

With Dr. In Lowe’s lab, immunologist Michel Sadeline, MD, PhD, and members of his lab were key collaborators on the study. Dr. Sadelain is a pioneer in the development of CAR T cell therapy, for which he was recently awarded the 2024 Breakthrough Prize in Life Sciences.

The study was led by Ines Fernandez-Maestre, a graduate student in the lab of MSK physician-scientist Ross Levin, and Karina Amor Vegas, MD, PhD, a former graduate student in the Lowe lab who now has her own lab in Cold Spring Harbor and is a corresponding author of the paper.

Targeting senescent cells with cART

A microscope image of an aged rat liver showing signs of chronic inflammation (dark purple cell clusters).

Sensitive cells are damaged cells that have gone into a protective, shutdown mode, where they stop dividing and actively send “help me” signals to the immune system. This may have some short-term benefits in contexts such as wound healing and preventing cell division that occurs in cancer, but it can cause chronic inflammation as senescent cells accumulate as people age.

In 2020, researchers at MSK identified a molecule on the surface of senescent cells that was largely absent in other types of cells. This allowed them to design CAR T cells that could recognize and attack that specific molecule, called the urokinase plasminogen activator receptor (uPAR). The team successfully tested the method in various mouse models of aging diseases, including cancer and liver fibrosis, according to the results they published. the nature.

New research also shows that senolytic (senescence-targeting) cell therapies can improve symptoms associated with aging.

UPAR-targeting cART cells provide an alternative to more conventional small-molecule drugs that are currently being investigated to clear senescent cells, Dr. Lowe, who is also an investigator at the Howard Hughes Medical Institute.

“A challenge with current small-molecule drugs is that many do not have a well-understood mechanism of action as it relates to aging. And many of them are repurposed cancer drugs with considerable toxicity.”

Such medicine should also be given repeatedly.

“However, T cells have the ability to develop memory and stay in your body for a really long time, which is very different from a chemical drug,” Dr. Amr Vegas, who was also co-first author on the previous study. “With cART cells, you have the possibility of getting this one treatment and then that’s it. For chronic pathologies, that’s a huge advantage. Think about patients who need multiple treatments per day and you get one infusion, and then you’re on it for years. Good to go.”

Furthermore, with a cellular therapy, it is possible to engineer safety features to target multiple molecules on the cell surface while minimizing side effects -; Reduce their chances of attacking healthy cells.

Using CAR T cells against cancer is different than challenging

Through these experiments, the research team was able to show: uPAR-positive cells increase with age and significantly contribute to aging-related dysfunction in tissues; uPAR-targeting CAR T cells can effectively eliminate senescent cells without major side effects in mice; and that administering treatment improves metabolic health in both normal aging and diet-related metabolic disease.

Mice typically live about two years, and studies have shown that uPAR-targeting CAR T cells persist and proliferate in mice for more than 15 months as they grow from youth to old age.

“In some ways, using CAR T cells to treat age-related diseases presents distinct challenges from using these therapies in cancer,” Dr. Low said. “If only a few cancer cells survive treatment, they can continue to divide to enable the tumor to repopulate. Because senescent cells do not divide, most are cleared but not all of them will still produce significant health benefits.”

Still, there is a high safety bar for developing therapies for diseases less lethal than cancer.

Dr. Sadeline said. “These efforts will undoubtedly expand the list of diseases that can be treated with cART cell therapy in the coming years.”

Source:

Journal Reference:

Amor, C., etc (2024). Prophylactic and chronic efficacy of senolytic cART cells against age-related metabolic dysfunction. Nature is aging. doi.org/10.1038/s43587-023-00560-5.



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