Chimeric antigen receptor (CAR) T cells are best known for their role in treating blood cancers. When used as an anticancer treatment, T cells are removed from an individual and engineered to boost their ability to target cancer cells before being returned to the body. The altered immune cells then seek out and destroy cancer cells with precision.
Now, scientists at Memorial Sloan Kettering are deploying CAR T cells against other diseases, including those caused by senescence, a chronic “alarm state” in tissues. The scope of ailments that this potential treatment could include are debilitating conditions such as fibrotic liver disease, atherosclerosis, and diabetes.
The work is published in Nature in the paper, “Senolytic CAR T cells reverse senescence-associated pathologies.”
The success of CAR T cell therapy depends on having a good target. The first FDA-approved CAR T cells target a molecule on the surface of blood cancers called CD19. It is present on cancer cells but few other normal cells, so side effects are limited.
Taking their cue from this prior work, a team of investigators sought to identify a target on senescent cells.
“Senescence is a double-edge sword,” said Scott Lowe, PhD, chair, cancer biology & genetics program, Sloan Kettering Institute (SKI) and a senior author on the paper. “Cells in this state play an important role in wound healing and cancer deterrence. But if they linger for too long, they can cause chronic inflammation, which itself is a cause of many diseases. Finding a way to safely eliminate these cells would be a major therapeutic breakthrough in the treatment of these diseases.”
Pathologically, the authors wrote, “the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes, and osteoarthritis.” They also wrote that eliminating senescent cells from damaged tissues in mice “ameliorates the symptoms of these pathologies and even promotes longevity.”
By comparing molecules on the surface of senescent cells to other cell types, the MSK scientists were able to identify a molecule—urokinase plasminogen activator receptor (uPAR)—that is enriched on these cells and mostly absent on others.
They then designed CAR T cells that recognize uPAR and tested them in several different mouse models of senescence-related diseases, including cancer and liver fibrosis. Fibrosis is a damaging process in which healthy tissue is gradually replaced by scar tissue and is a major cause of liver disease.
The engineered cells successfully eliminated senescent cells from two different mouse models of liver fibrosis. As well, the CAR T cells improved survival in mouse models of lung cancer when given along with drugs previously shown to induce senescence in this cancer type.
The team’s next step will be to determine whether the uPAR-directed CAR T cells can effectively combat other senescence-related diseases, including atherosclerosis, diabetes, and osteoarthritis. Eventually, they hope to develop the cells for clinical use in people.
“This study demonstrates that T cell engineering and CAR therapy can be effective beyond cancer immunotherapy,” said Michael Sadelain, MD, PhD, director of the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center (MSKCC), whose lab pioneered the first effective CAR T cells against cancer.
“We think this approach has the potential to tackle a number of senescence-related diseases for which new treatments are badly needed,” Lowe added.