Immunotherapy kills pathogen cells in mice with MS-like disease |  Washington University School of Medicine in St. Louis

Immunotherapy kills pathogen cells in mice with MS-like disease | Washington University School of Medicine in St. Louis

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Successful approach to cancer treatment extended to autoimmune diseases

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The cancer therapy known as CAR-T has revolutionized the treatment of certain blood cancers since its introduction in 2017. The therapy uses genetically modified immune cells to focus on and destroy cancer cells.

Now, by studying mice with an autoimmune disease similar to multiple sclerosis (MS), researchers at Washington University School of Medicine in St. Louis have shown that the same approach can be used to eliminate cells. undesirables that cause autoimmunity. The results, available online in Science Immunology, extend the powerful tool of immunotherapy to a class of often debilitating and difficult-to-treat diseases.

“We were able to use CAR-T cells to only kill the immune cells that cause autoimmunity and not other immune cells that you might need to protect yourself against viruses or other infections,” said the senior co-author Chyi-Song Hsieh, MD, PhD, Alan A. and Edith L. Wolff Professor of Rheumatology, and Professor of Medicine, Pathology, and Immunology. “Our CAR-T cells were very effective in treating mice with an MS-like disease.”

At the heart of CAR-T therapy are the T cells of the immune system, crucial elements of the body’s defense force. T cells respond to threats such as bacteria, viruses, and cancer cells by coordinating an immune attack and killing foreign organisms and infected or cancerous cells.

But every once in a while, T cells mistake healthy cells for infected cells and turn their weapons against the body’s own cells and tissues, triggering an autoimmune disease. MS is marked by rogue T cells that trigger the destruction of myelin, the protective covering of nerves. As the myelin is eaten away, communication between the brain and spinal cord and the rest of the body becomes unreliable, and people begin to experience symptoms such as fatigue, pain, tingling, vision problems, and loss. coordination. Immunosuppressive drugs can nullify the self-destructive activity of rogue T cells, but these drugs also suppress helpful T cells and put people at risk for serious infections.

In CAR-T cancer therapies, doctors take a patient’s own T cells, modify them to recognize and vigorously attack their specific cancer, then inject them back into the body as part of a mission to research and destruction. Inspired by this approach, researchers set out to create CAR-T cells equipped to seek out and destroy the rogue T cells that cause MS. The idea was to make CAR-T cells that would function like a police department’s internal affairs office, taking out the bad apples from the T-cell defense force while leaving good T-cells in place to protect the body.

“MS can really erode your quality of life, and although current therapies slow the progression of the disease, they don’t cure it, and they have side effects,” said co-senior author Gregory F. Wu, MD, PhD, Associate Professor of Neurology and Pathology and Immunology. “I believe this is a fully treatable disease, and CAR-T cells could be the pathway to much better therapies.”

Along with Hsieh and Wu, the research team included co-authors Nathan Singh, MD, assistant professor of medicine, and Takeshi Egawa, MD, PhD, associate professor of pathology and immunology.

First, the researchers made bait. They engineered a molecule by combining a fragment of a protein found in myelin with a protein that activates T cells. Only T cells that target myelin—black sheep, so to speak—would respond to this hybrid molecule. Then they loaded the bait molecule onto a kind of T cell known as killer T cells. Any rogue T cells that took the bait would be eliminated by the killer T cells.

That was the idea, at least. To see if it worked, the researchers turned to mice with an MS-like disease. Treating these mice with the modified CAR-T cells prevented disease in those who had not yet developed problems and reduced signs of disease in those who already showed neurological effects.

“We are working on improving CAR-T cells, to get them to kill more efficiently and last longer so that we can get better treatment results,” Hsieh said. “Right now there’s no way of knowing who’s going to get MS or when, so preventing the disease in people isn’t realistic, but we could treat it, and I think the CAR- T looks very promising.”

The beauty of the CAR-T approach is that by swapping the protein fragment in the bait molecule, killer T cells can be redirected to different rogue immune cells to treat different diseases.

“I see patients in the clinic who have a rare disease known as myelin oligodendrocyte glycoprotein antibody (MOG) disease which is very similar to MS,” Wu said. , which is complicated, we know exactly what is the target in MOG antibody disease. I wish I could get rid of these autoreactive cells for my patients, but we have no way to do that. Now we are working on using the patient’s own immune cells to create CAR-T cells that would eliminate these self-reactive T cells.

Yi J, Miller AT, Archambault AS, Jones AJ, Bradstreet TR, Bandla S, Hsu YS, Edelson BT, Zhou YW, Fremont DH, Ego T, Singh N, Wu GF, Hsieh CS. Antigen-specific depletion of CD4+ T cells by CAR T cells reveals distinct roles of higher and lower affinity TCRs during autoimmunity. Immunology Sciences. October 7, 2022. DOI:10.1126/sciimmunol.abo0777

This study was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH), grant number R01NS106289; the National Multiple Sclerosis Society, grant numbers RG-1802-30253 and RG-2111-38724; the National Institute of Allergy and Infectious Diseases, grant numbers R01-AI07987 and R01AI165771; the National Cancer Institute, grant number K08CA237740; and the Wolff Chair.

About Washington University School of Medicine

WashU Medicine is a world leader in academic medicine, including biomedical research, patient care, and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% over the past five years, and with institutional investment, WashU Medicine dedicates more a billion dollars a year for basic and clinical research. innovation and training. Its faculty practice is consistently ranked among the top five in the nation, with more than 1,790 faculty physicians practicing at more than 60 sites who also serve on the medical staff of BJC HealthCare’s Barnes-Jewish and St. Louis Children’s Hospitals. WashU Medicine has a rich history of MD/PhD training, recently dedicated $100 million in scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physiotherapy, occupational therapy, and audiology and communication sciences.

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