CAR T cells target senescent cells, improve lifespan in mice

Chimeric antigen receptor (CAR) T cells have transformed the treatment of blood cancers in recent years. And there have been positive signs that “living medicines” can be harnessed 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 also hold promise for treating certain diseases associated with aging. Specifically, those caused by the accumulation of senescent cells (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 aged and prematurely aging mice from a high-fat diet, but a dose given to young, healthy mice also helped preventing metabolic decline later. life, according to findings published by the research team in Aging Nature.

When you hear ‘CAR T cell therapy’, do you think ‘cancer’ -? and it makes sense that it was first introduced in a place like MSK. But what we’re learning is that this approach to engineering immune cells to target disease has much broader potential.”

Scott Lowe, PhD, senior study author, Chair of the Cancer Biology and Genetics Program at MSK’s Sloan Kettering Institute

CAR T therapy improves metabolic function in mice

In the study, younger mice were fed a high-fat diet for two months, which made them obese and caused metabolic stress. After injecting the experimental CAR T cells, the mice had lower body weight, better fasting blood glucose levels, and improved glucose and insulin tolerance, despite continuing the high-fat diet. They also had fewer senescent cells in their pancreas, liver and adipose tissue than mice in a control group. Similar results were seen in older mice where metabolic function had declined due to natural aging.

The older mice that received the treatment took longer to exhaust during exercise. And the approach didn’t seem to cause any significant side effects.

Further research is needed to see if the approach could extend the lifespan of the mice in addition to improving their ‘span of health’ -? that is, how long they remain healthy and disease-free, the scientists note.

“We continue to learn new things about aging at the biological level,” says Dr. Lowe. “It will take time, but we are interested in working with industry partners to move laboratory findings into clinical trials.”

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

Along with Dr. Lowe’s lab, immunologist Michel Sadelain, MD, PhD, and members of his lab were key collaborators on the research. 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 co-led by Inés Fernández-Maestre, a graduate student in the lab of MSK physician-scientist Ross Levine, MD, and by Corina Amor Vegas, MD, PhD, a former graduate student in the Lowe Lab who now leads it. own laboratory in Cold Spring Harbor and is the corresponding author of the paper.

Targeting senescent cells with CAR T

Microscope image of an aged mouse liver showing signs of chronic inflammation (clusters of dark purple cells).

Senescent 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 things like wound healing and preventing the runaway cell division that occurs in cancer, but it can also lead to 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 from other cell types. This allowed them to engineer CAR T cells that could recognize and attack this particular molecule, called the urokinase plasminogen activator receptor (uPAR). The team successfully tested the approach in several different mouse models of aging-related diseases, including cancer and liver fibrosis, according to findings they published in Nature.

New research goes further by demonstrating that senolytic (aging-targeting) cell therapies can improve aging-related symptoms.

CAR T cells that target uPAR provide an alternative to the more traditional small-molecule drugs currently being investigated to clear senescent cells, notes Dr. Lowe, who is also a Howard Hughes Medical Institute investigator.

“One of the challenges with current small-molecule drugs is that many do not have a well-understood mechanism of action in terms of aging. And many of them are anticancer drugs with significant toxicity.”

Such drugs must also be administered repeatedly.

“T cells, however, have the ability to develop memory and persist in your body for very long periods, which is very different from a chemical drug,” notes Dr. Amor Vegas, who was also first author on the previous study. . “With CAR T cells, you have the ability to get that treatment, and then that’s it. I’m good to go for many years.”

In addition, with a cellular therapy, it is possible to design safety features to mitigate side effects as well as simultaneously target multiple molecules on the cell surface -. reducing the chances of them attacking healthy cells.

Different challenges of using CAR T cells against cancer

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

Mice normally live about two years, and the research found that CAR T cells targeting uPAR persisted and expanded for more than 15 months in the mice as they grew from young to older age.

“In some ways, using CAR T cells to treat age-related diseases presents separate challenges than using these therapies in cancer,” says Dr. Lowe. “If only a few cancer cells survive treatment, they may continue to divide to allow the tumor to relapse. Since senescent cells do not divide, clearing most but not all of them should produce significant health benefits.”

However, there is a high level of safety in developing treatments for diseases that are less lethal than cancer.

“We continue to develop new strategies to engineer cell therapies to be less toxic and less expensive,” says Dr. Sadelain. “These efforts will undoubtedly expand the list of diseases that can be treated with CAR T cell therapies in the coming years.”