Other research has looked at CAR-T cells' ability to clear senescent cells, but the new study suggests they could be both prophylaxis and a treatment for metabolic changes associated with aging.
Researchers have successfully used chimeric antigen receptor T (CAR T) cells to prevent some signs of aging in young mice and reverse them in old ones, building a case for the therapy’s place in longevity research and regenerative medicine.
In a study published Jan. 24 in Nature, researchers from Cold Spring Harbor Laboratory in New York described how they used CAR T therapy to clear out senescent cells—cells that stop dividing but don’t undergo apoptosis, or cell death—in both young and old mice. The treatment staved off or improved signs of metabolic disease. The findings broaden CAR-T cells’ theoretical indications and demonstrate the possibility that they can persist long term even after just one treatment, first author Corina Amor Vegas, M.D., Ph.D., told Fierce Biotech Research in an email. “In particular, I think the concept that they can develop persistence and mediate effects for long periods of time after a single administration is very interesting for the treatment of chronic pathologies in which patients currently have to receive multiple daily treatments,” she said.
Senescent cells are one of the main villains in longevity researchers’ fight against aging. While non-dividing cells are essential for wound healing, embryo development and tumor suppression, as a 2022 review in Nature Nephrology explains, their accumulation over time seems to be linked to many pathologies of aging: Research has implicated senescent cells in a less-effective immune response, inflammation, strokes, cardiovascular disease, Alzheimer’s disease and more. This evidence has given rise to a class of drugs called senolytics, which proponents believe can combat or even reverse some forms of age-related disease by eliminating senescent cells. The new work from Amor Vegas’ team suggests it might be possible to use CAR-T therapy to prevent them from building up in the first place. In one set of experiments, her lab gave a single dose of CAR-T cells targeting the antigen urokinase plasminogen activator receptor, or uPAR, to three-to-four month old mice—roughly 20 years old in human years—then followed them for up to a year post-treatment. The mice that received the therapy were metabolically healthier and more active than their same-aged, untreated counterparts. They also had less buildup of senescent cells in organs throughout their bodies. The therapy was rejuvenating for older mice too: The researchers gave the same type of CAR T-cells to mice between the ages of 18 and 20 months, equivalent to about 60 years old in humans. Treated mice had lower levels and biomarkers related to “inflammaging”, a phenomenon where senescent cells induce chronic inflammation that ultimately leads to age-related disease. Like the young mice, they also had improved metabolic profiles compared to the mice that didn’t receive the therapy. Neither group suffered off-target effects or adverse effects from the treatment.
“Collectively, these results show that uPAR CAR-T cells can safely and effectively remove senescent uPAR-positive cells in the tissues of naturally aged mice and ameliorate age-dependent metabolic and physical dysfunction,” the research team wrote in their paper. This isn’t the first time researchers have used CAR-T therapy to clear dormant cells. In August 2023, a team of scientists led by researchers from Sichuan University in China reported that CAR-T cells targeting the antigen NKG2DL successfully eliminated senescent cells in mice. Amor Vargas’ team has done something similar before too: Back in 2020, her team used CAR-Ts targeting uPAR to remove senescent cells from mice with liver cancer, lung cancer and liver fibrosis. The new study is different in that it looks at CAR-T therapy both as a prophylaxis and a treatment for changes associated with aging. Furthermore, the cells’ persistence demonstrates that even one administration might be able to treat chronic, age-related conditions.
“The persistence of the uPAR-targeted CAR-T cells and the durability of the effects after a single low-dose treatment highlight the clinical potential of the senolytic CAR T cell approach for the treatment of chronic pathologies,” the researchers wrote in their paper. Still, many unanswered questions remain. While the researchers could verify that the treatment removed senescent cells, it’s not yet clear exactly which other populations benefited and contributed to the metabolic improvements the researchers saw, they noted in the paper. The clinic is still a distant goal, perhaps even more so with concerns about secondary T cell cancers linked to CAR-T therapy. “Of course, this is still a proof of concept in animals,” Amor Vargas said. “There is still a really long way to go to even consider similar approaches in humans."