Abstract: Chimeric antigen receptor T (CAR-T) cells have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy for tumor treatment. However, recent study found it may also be efficient in aging-related disease, such as liver fibrosis.
On June 17, 2020, the research team of Memorial Sloan Kettering Cancer Center announced that chimeric antigen receptor T (CAR-T) cell therapy can be used to treat diseases caused by aging, such as liver fibrosis. This research result is published in Naturetitled Senolytic CAR T cells reverse senescence-associated pathologies.
CAR-T technology was first studied for cancer therapy research. Immunotherapy has become a revolution in the field of cancer treatment. Compared with traditional methods such as radiation and chemotherapy, immunotherapy is more specific with less toxicity. CAR-T cell therapy is the most promising method among various kinds of immunotherapies, which has shown the ability to eliminate various tumors, especially for B cell malignancies, with a remission rate of up to 95%.
CAR T-cell therapy is an immunotherapy that uses genetically engineered T cells to target cancer cells. It is to extract T cells from the blood of the patient (or other people), and then they are genetically engineered to express chimeric antigen receptors (CARs) on their surfaces. When these CAR-T cells with recognition function are re-injected into the patient's body, they can recognize and attack cancer cells in the human body, thereby achieving the effect of killing cancer.
“Currently, there are two FDA-approved CAR-T cell therapies, Novartis’ Kymriah for the treatment of acute lymphoblastic leukemia and Gilead’s Yescarta for the treatment of large B-cell lymphoma.” as introduced by a scientist from Creative Biolabs, a biotech company focusing on CAR-T therapy development services.
And now, CAR-T technology also shows its glamour in diseases caused by aging. Cell senescence refers to a state of cell cycle arrest, in which proliferating cells will be resistant to growth-promoting stimuli and will not continue to proliferate. Cell senescence is a double-edged sword. On the one hand, it can prevent the replication of cells containing damaged DNA and play an important anti-tumor function. On the other hand, it can cause many related diseases, such as cancer, tissue degeneration and inflammatory diseases. Finding a safe way to clear senescent cells will be a major breakthrough in the treatment of these diseases.
Based on these characteristics, researchers at Memorial Sloan Kettering Cancer Center began their research on cellular aging. They compared the molecules on the surface of senescent cells and other types of cells and found that a molecule called urokinase plasminogen activator receptor (uPAR) is widely present on the surface of senescent cells, but rarely appears on the surface of other cells. Experiments have confirmed that uPARsare expressed at a high level in the tissues of patients suffering from elderly-related diseases (such as osteoarthritis, diabetes, and fibrotic liver disease). Therefore, they designed CAR-T cells that can recognize uPARs.
The researchers injected mice with lung cancer with CDK4/6 inhibitors for lung cancer plus CAR-T cells targeting uPARs, and CDK4/6 inhibitors plus untransfected T cells. The results showed that the group of CDK4/6 inhibitor and uPAR-targeted CAR-T cell therapy significantly prolonged the survival time of mice without any toxicity. The researchers also used CAR-T cells that target uPARs to treat lung tissue containing lung tumor cells and found that the number of tumor cells in an aging state decreased significantly.
In addition to cancer, the researchers also studied the effects of CAR-T cells on liver fibrosis and found that CAR-T cells successfully eliminated senescent cells in two different liver fibrosis mouse models. They said they will continue to study the application of uPAR-targeted CAR-T cells in other aging-related diseases, such as atherosclerosis, diabetes and osteoarthritis, and hope to develop CAR-T cells for human clinical use.
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