Novel CAR T-cell Therapy Shows Promise in MS Mouse Study
It eliminates the immune cells that drive MS, but not healthy immune cells
Researchers have developed a technique that uses CAR T-cells, a form of cell therapy, to specifically eliminate the self-reactive immune cells that drive multiple sclerosis (MS), without destroying healthy immune cells needed to protect against infection.
“Our CAR-T cells were very effective at treating mice that have an MS-like disease,” Chyi-Song Hsieh, MD, PhD, a professor at Washington University School of Medicine and co-senior author of the new study, said in a university press release.
“I believe that this is a fully treatable disease, and CAR-T cells may be the way toward much better therapeutics,” added co-senior author Gregory Wu, MD, PhD, also a professor at Washington, in St. Louis, Missouri.
The study, “Antigen-specific depletion of CD4+ T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity,” was published in Science Immunology.
T-cells are a group of immune cells that are equipped with a specialized receptor that very specifically recognizes a particular molecular target — for example, a piece of a virus or bacteria — referred to as an antigen.
A group of immune cells called antigen-presenting cells (APCs) are responsible for “presenting” the potential antigens to T-cells, making them highly specific against that target. Then, when a T-cell comes in contact with its specific antigen, it activates the cell to go on the attack, spewing out pro-inflammatory molecules to sound the alarm.
When the T-cell is recognizing part of a virus or bacteria, this can help clear an infection. In MS, however, T-cells will react to healthy components of the myelin sheath, a fatty coating around nerve fibers needed for their function.
There are a number of approved disease-modifying therapies for MS that deplete or reduce the activity of T-cells, but these therapies generally affect both disease-driving cells and infection-fighting cells indiscriminately. Here, researchers developed a method aiming to eliminate only the self-reactive T-cells using another kind of T-cell: CAR T-cells.
Conceptually, CAR T-cells are created by taking normal T-cells, removing their native receptor, and equipping them with a new, human-made molecular receptor called a CAR (an abbreviation for chimeric antigen receptor). Since the CAR is lab-made, scientists can create new receptors aiming to direct the cells to attack specific antigens. This approach has been widely explored in cancer, equipping the cells with CARs that will direct them to attack and kill tumor cells.
CAR T-cell therapy and MOG
To create CAR T-cells that specifically could kill self-reactive T-cells, the scientists engineered a CAR that would look just like the myelin oligodendrocyte glycoprotein (MOG), a myelin protein, being presented by an APC.
The idea is that this receptor would act as “bait,” specifically targeting the MS-driving T-cells with receptors that react to this self-antigen. By the same principle, the receptor wouldn’t have any effect on T-cells that don’t react with myelin.
“We were able to use CAR-T cells to eliminate just the immune cells that are causing the autoimmunity and not other immune cells you might need to protect against viruses or other infection,” Hsieh said.
The researchers tested their CAR T-cells in mice with experimental autoimmune encephalitis, a common mouse model of MS. The team found that pre-treatment with their cells could prevent the development of the disease. However, in initial attempts, the cell therapy did not lessen existing disease.
Analyses showed that the initial CAR could bind to T-cells with high-affinity receptors for MOG, but wasn’t binding as well to cells with lower-affinity receptors. Essentially, the CAR was not “sticking” to some myelin-reactive T-cells.
The researchers made molecular modifications to their initial CAR to make it “stickier” for these cells. These modified CARs could effectively bind to both high-affinity and low-affinity receptors.
In the EAE models, treatment with CAR T-cells carrying this upgraded receptor was able to prevent EAE from developing, and unlike the initial attempts, they also were able to reverse ongoing clinical EAE, the researchers said.
‘Activation energy’
“These data suggest a model in which higher-affinity [self-reactive] T cells are required to provide the ‘activation energy’ for initiating neuroinflammatory injury, but lower-affinity cells are sufficient to maintain ongoing disease,” the scientists wrote.
“We’re working on improving the CAR-T cells, to get them to kill more efficiently and last longer so that we can get better treatment outcomes,” Hsieh said. “Right now, there’s no way to tell who is going to get MS or when, so preventing disease in people isn’t realistic, but we could treat it, and I think the CAR-T approach looks very promising.”
The scientists noted that this approach also could be applied in other autoimmune diseases by making CARs that mimmic other antigens.
“I see patients in the clinic who have a rare disease known as myelin oligodendrocyte glycoprotein (MOG) antibody disease that is very similar to MS,” Wu said. “Unlike MS, which is complicated, we know exactly what the target is in MOG antibody disease. I wish I could just get rid of these self-reactive cells for my patients, but we’ve had no way to do that. Now, we are working toward using the patient’s own immune cells to create CAR-T cells that would eliminate those self-reactive T cells.”
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