Can CAR-T Cells Be Used to Treat Diseases like Diabetes and Fibrosis?

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An immunotherapy, chimeric antigen receptor T-cell (CAR-T), has revolutionized certain types of cancer treatments. The two approved CAR-T therapies are Novartis Kymriah (tisagenlecleucel) and Gilead Sciences’ Yescarta (Axicabtagene ciloleucel). They are essentially living therapies. They are drawn from a patient, engineered in a lab to focus more closely on the specific cancer, and reinfused into the patient where the cells grow and attack the cancer cells.

New research out of the Memorial Sloan Kettering Cancer Center suggests the genetically engineered immune cells can be used to treat diseases of senescence, which could include fibrotic liver disease, atherosclerosis, and diabetes.

Cellular senescence is a kind of “zombie” state related to aging, where cells stop dividing and growing, but don’t actually die. It is particularly associated with diseases of aging.

“Senescence is a double-edge sword,” said Scott Lowe, chair of the Cancer Biology and Genetics Program at the Sloan Kettering Institute and co-responding author on the study. “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.”

The research was published in the June 17 issue of the journal Nature.

The research team compared molecules on the surface of senescent cells to other types of cells. They identified a molecule called urokinase plasminogen activator receptor (uPAR) that was enriched on the senescent cells, but largely absent on other cells. They then designed CAR-T cells that recognized uPAR.

Evaluating these newly engineered cells on mouse models of senescence-related diseases, such as cancer and liver fibrosis, they found that CAR-T cells successfully eliminated senescent cells from two different mouse models of liver fibrosis. The CAR-T cells also improved survival in lung cancer mouse models when dosed with drugs that induced senescence in this type of cancer.

The researchers plan to continue studying uPAR-directed CAR-T cells in other senescence-associated diseases, such as atherosclerosis, diabetes, and osteoarthritis, with hopes of developing them for clinical use in humans.

“This study demonstrates that T-cell engineering and CAR therapy can be effective beyond cancer immunotherapy,” said Michel Sadelain, director of the Center for Cell Engineering at Sloan Kettering.

Lowe added, “We think this approach has the potential to tackle a number of senescence-related diseases for which new treatments are badly needed.”

Senescence has been a growing field in the last few years. South San Francisco-based Unity Biotechnology focuses on senescence to halt, slow or reverse age-associated diseases. The company’s pipeline includes UBX0101, which is in Phase II trials for osteoarthritis and UBX1967 and UBX1325 for age-related macular degeneration, diabetic macular edema, and diabetic retinopathy. Other programs are studying idiopathic pulmonary fibrosis, liver and kidney diseases, and neurodegenerative and cognitive disorders.

On March 31, the company announced that it had completed enrollment in its UNITY Phase II trial of UBX0101 in moderate-to-severe osteoarthritis of the knee. It was evaluating 183 patients and expects to report results in the second half of 2020

Research that came out of Rockefeller University last year found that, unexpectedly, the neurons affected by Parkinson’s disease may actually be senescent and that these “undead neurons” release molecules that shut down neighboring brain cells that lead to common Parkinson’s symptoms.

Senescent cells occur throughout the body, but it is not usually seen in nerve cells in the brain. Neurons halt division once fully formed. But the research group found that dopamine neurons that regulate motivation, memory and movement by producing dopamine can become senescent.

Similarly, in 2018, researchers at the University of Texas Health Science Center at San Antonio found cellular senescence was linked to tau protein tangles associated with end-stage Alzheimer’s disease. Cellular senescence can be a survival strategy for cells under stress, but it can also cause cells to behave abnormally and secrete toxins that kill surrounding cells.

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