CAR T cells show promise against age-related diseases in mice

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

Now, laboratory research led by Memorial Sloan Kettering Cancer Center (MSK) and Cold Spring Harbor Laboratory is showing that these genetically engineered immune cells can be used to treat several aging-related diseases, especially aging. It also suggests promise in treating diseases caused by the accumulation of inactive cells. (split due to aging, damage, etc.)

Infusions of CAR T cells designed to target senescent cells can not only improve metabolic function in older mice or mice aged prematurely on a high-fat diet, but also when administered in a single dose to young, healthy mice. It also helped prevent subsequent metabolic decline.According to findings published by the research team in 2016, life is natural aging.

“When you hear the words ‘CAR T-cell therapy,’ you think of cancer, and it’s no surprise that it was pioneered at a place like MSK,” said lead study author and professor of cancer biology and genetics. said Dr. Scott Lowe, chair of the academic program. MSK’s Sloan Kettering Institute. “But what we are learning is that this approach to manipulating immune cells to target disease has much broader potential.”

In the study, feeding young mice a high-fat diet for two months made them obese and caused metabolic stress. After being injected with experimental CAR T cells, the mice lost weight, had improved fasting blood sugar levels, and improved glucose tolerance and insulin resistance, despite being kept on a high-fat diet. There were also fewer senescent cells in the pancreas, liver, and adipose tissue than in control mice. Similar results were seen in older mice, where metabolic function declines due to natural aging.

Older treated mice took longer to fatigue during exercise. And this approach didn’t seem to cause any serious side effects.

Further research is needed to see if this approach can extend the lifespan of mice, as well as improve their “healthspan” – how long mice can stay healthy and free from disease. scientists point out.

“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 test results into clinical trials.”

Diseases associated with aging and chronic inflammation, such as chronic obstructive pulmonary disease (COPD), nonalcoholic steatohepatitis (NASH), osteoarthritis, metabolic syndrome, and even certain neurodegenerative diseases, have potential It could be effective, Dr. Lowe says.

Along with Dr. Lowe’s lab, immunologist Michel Sadran, MD, PhD, and members of his lab were key collaborators on the study. Dr. Sadlein is a pioneer in the development of CAR T-cell therapies and was recently awarded the 2024 Life Sciences Breakthrough Award for his work.

The study was led by Ines Fernández Maestre, a graduate student in the lab of MSK physician-scientist Ross Levine, M.D., Ph.D., and Corinna Amor Vegas, M.D., a former graduate student in the Lowe lab and her current director. Co-led by Dr. He is affiliated with his own laboratory in Cold Spring Harbor and is the corresponding author of this paper.

Targeting senescent cells with CAR T

Senescent cells are cells that have been damaged and enter a protective shutdown mode, where they stop dividing and actively send “help” signals to the immune system. This may have 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 we age. there is.

In 2020, MSK researchers identified a molecule on the surface of aging cells that is rarely present on other cell types. This has made it possible to engineer CAR T cells that can recognize and attack a specific molecule called urokinase plasminogen activator receptor (uPAR). The research team successfully tested this approach in several different mouse models of aging-related diseases such as cancer and liver fibrosis. Nature.

New research goes further in demonstrating that senolytic (senescence-targeting) cell therapy can improve symptoms associated with aging.

CAR T cells that target uPAR offer an alternative to more traditional small molecule drugs currently being investigated to eliminate senescent cells, said Dr. Lowe, who is also a Howard Hughes Medical Institute investigator.

“One of the challenges with current small molecule drugs is that many drugs are associated with aging and their mechanisms of action are not well understood. It’s a reused agent.”

These drugs also require repeated administration.

“However, T cells have the ability to develop memory and persist in the body for very long periods of time, which is very different from chemicals,” said Dr. Amor Vegas, co-lead author of the previous study. Point out. . “With CAR T cells, you only need one treatment and that’s it. For chronic conditions, this is a huge advantage. Think about patients who need multiple treatments a day. If you are on an IV, you can receive treatment for many years.”

Additionally, cell therapies can incorporate safety features to reduce side effects while targeting multiple molecules on the cell surface, reducing the chance of attacking healthy cells.

Different challenges from using CAR T cells in cancer

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

Mice typically have a lifespan of about two years, and the study found that CAR T cells that target uPAR persisted for more than 15 months and proliferated as the mice grew from young to old age.

“In some ways, using CAR T cells to treat age-related diseases presents distinctly different challenges than using these therapies for cancer,” Dr. Lowe says. “If only a small number of cancer cells survive treatment, they may continue to divide and the tumor may return. Senescent cells do not divide, so even if most, if not all, of the cells are removed, There are considerable health benefits.”

Still, there are high safety standards for developing treatments for diseases less deadly than cancer.

“We continue to develop new strategies to engineer cell therapies to be less toxic and less expensive,” says Dr. Sadlein. “These efforts will no doubt expand the list of diseases that can be treated with CAR T-cell therapy in the coming years.”

Additional author, funding, and disclosure information

Other authors include Saria Chowdhury, Sandeep Nadella. Emanuela Nnuzi John and David Tubson of Cold Spring Harbor Laboratory; MSK’s Mr. Yu Jui Ho, Mr. Courtney Graham, Mr. Clemens Hinterleitner, Mr. Valentin J.A. Barthe, Mr. Riccardo Mezzadra, and Mr. Matthew Weleski. Sebastian Carrasco of MSK, Weill Cornell Medicine, and Rockefeller University; MSK and his Judith Feucht of the University Children’s Hospital Tübingen, Germany; Lee Jones of MSK and Weill Cornell Medicine; and Jacob Boyer of Princeton University.

This study was funded in part by the National Institutes of Health (5P30CA45508, U01CA210240, R01CA229699, U01CA224013, 1R01CA188134, 1R01CA190092, S10OD028632-01) and the National Cancer Institute (CA197594, 5P30CA04). 5508, P30CA008748, P30CA045508), and National Institute on Aging (U01AG077925, AG065396, 1R01AG082800-01). See our research for a complete list of funders.

Doctors. Amor Vegas, Feucht, Sadelain, and Lowe are listed as inventors on several patent applications related to senolytic CAR T cells. Doctors. Amor Vegas, Sadelain and Lowe are advisors to Fate Therapeutics. Several others report service on scientific advisory boards for pharmaceutical companies or consulting work. Please see the study for a complete list of disclosures.

Read the article: “Preventive and long-term effects of senolytic CAR T cells against age-related metabolic dysfunction,” natural aging. DOI: 10.1038/s43587-023-00560-5