Many age-related diseases such as liver fibrosis, atherosclerosis, diabetes and osteoarthritis have been partly attributed to cellular "senescence," a zombie-like state in which cells stop proliferating but remain alive. Could CAR-T therapy, which involves genetically editing patients' own immune cells, treat those diseases by targeting senescent cells?
Researchers at Memorial Sloan Kettering Cancer Center have set out to answer that question. They designed CAR-T cells that target a protein called urokinase plasminogen activator receptor (uPAR) on the surface of senescent cells. The CAR-T cells worked in mouse models of liver and lung cancers and liver fibrosis, the team reported in Nature.
“Senescence is a double-edge sword,” the study’s co-corresponding author Scott Lowe explained in a statement. “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.”
Clearing accumulated senescent cells has emerged is a new field in drug research called "senolytics." For example, California’s Unity Biotechnology is working on several senolytic drugs to treat age-related diseases, including one in collaboration with China’s Ascentage Pharma to address a range of eye disorders.
But for CAR-T cells to work as senolytics, the Memorial Sloan Kettering researchers first needed to identify an antigen on senescent cells that the CAR (chimeric antigen receptor) could target. The two CAR-T treatments on the market now, blood cancer drugs Kymriah from Novartis and Yescarta from Gilead Sciences, are directed at the antigen CD19 on cancer cells.
By screening molecules on the surface of cells in both mice and humans, the Memorial Sloan Kettering team found that uPAR was highly expressed on senescent cells but was mostly absent in normal tissue.
After designing uPAR-specific CAR-T cells, Lowe's team decided to test them in premalignant cells that typically undergo senescence. In mouse models of liver and lung cancer, the team found that the CAR-T cells successfully cleared these premalignant senescent cells. The treatment significantly prolonged survival in the lung cancer models.
In a mouse model of liver fibrosis marked by the accumulation of senescent cells in the liver, treatment with the uPAR-directed CAR-T cells significantly reduced liver scarring when compared to control animals. Blood levels of liver enzymes also dropped, indicating improved liver function. Similar results were observed in fibrosis induced by non-alcoholic steatohepatitis, or NASH, a liver condition many biopharma companies have tried to tackle but failed.
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Several other research groups are investigating T-cell approaches for treating inflammatory diseases. Scientists at the University of Pennsylvania developed chimeric "autoantigen" receptor (CAAR) T cells that target rogue antibodies against the muscle-specific kinase to treat myasthenia gravis. A team at the University of Tennessee has investigated a CAR-T treatment that targets the harmful B cells behind lupus.
Recently, scientists from the Seattle Children’s Research Institute and the Benaroya Research Institute transformed CD4 T cells into cells with immunosuppressive properties with the goal of controlling the autoimmune response in Type 1 diabetes.
The Memorial Sloan Kettering team is hopeful their uPAR-directed senolytic CAR-T cells hold potential for treating several senescence-related diseases associated with aging. They're now planning to test the therapy in atherosclerosis, diabetes and osteoarthritis.