For the first time, an off-the-shelf CAR T-cell therapy has been used to treat a potentially life-threatening autoimmune disease. With just one injection, the treatment quickly reversed debilitating symptoms for up to a year.
This treatment transformed one recipient’s life. A 57-year-old man (Mr. Seong Gong) who was diagnosed with systemic sclerosis, an autoimmune disease that destroys muscles and joints, regained his life two weeks after receiving the injection. He could move the muscles around his mouth when he smiled. His fingers danced across the keyboard again at work.
A year later he said: nature“I feel great.”
Gong is part of an ongoing clinical trial to genetically reprogram healthy donor cells into a universal “living drug.” The trial, scheduled to end in 2025, could overturn current interventions for the incurable autoimmune disease. This lifelong disease is mostly managed with immunosuppressants, but is not curable. Although helpful, medications can greatly reduce a person’s ability to fight off infectious diseases, making it difficult to fight off bacterial or viral attacks.
Chimeric antigen receptor (CAR) T cell therapy takes a different approach.
Immune cells, here called T cells, are genetically engineered to hunt targets inside the body, including malignant immune cells that destroy the body’s own tissues. Treatment is usually tailored to each person. New research suggests that personalization isn’t always necessary. We may be able to mass-produce living drugs in the future, reducing costs.
CAR T Refresher
CAR T therapy is perhaps best known for its groundbreaking ability to treat previously untreatable blood cancers.
Here’s how it generally works: A patient’s immune cells are extracted and genetically manipulated to produce specific protein “guides” that attach to the surface of each cell. This guide helps cells detect cancer and alerts the body’s immune system to increase its attack.
This is a game-changer for blood cancer. The FDA has already approved six CAR T therapies. The latest research has attempted to directly reprogram immune cells inside the body. The authors wrote that the treatment “has been hailed as one of the greatest innovations of all time.”
But CAR T has more tricks up its sleeve. For nearly a decade, scientists have believed the drug could treat autoimmune diseases that cause the immune system to attack itself in a fight.
This is a story about two types of immune cells: T cells and B cells. Normally, B cells capture invading pathogens and pump out antibodies that tag them for elimination. But in autoimmune diseases, healthy tissue is marked as an enemy, alerting T cells to destroy it and causing the body to attack itself. CAR T cells that target these defective B cells could solve autoimmune problems in the bud.
Making your body fight sounds irrational, but the idea seems to work. A treatment for antisynthetic enzyme syndrome, an autoimmune disease that damages the lungs and muscles, improved the patient’s breathing and mobility in just three months. Similar treatments have also been used to treat pemphigus vulgaris, a fatal autoimmune disease that causes the skin to gradually peel off.
Despite these promises, CAR T has its problems. Because each treatment is tailored to the individual, the process can be costly and time-consuming. Currently approved treatments cost hundreds of thousands of dollars in the United States. India is making cutting-edge CAR T treatments for cancer at about a tenth of the cost, but low-cost treatments are not available for autoimmune diseases.
One way to cut costs and accelerate production is to stop personalization altogether. A more efficient way to make CAR T cells is to use immune cells from healthy donors. Like the plug-and-play Mr. Potato head, cells can be given genes that increase immune attacks against cancer cells or suppress friendly attacks caused by autoimmune attacks.
plug and play
In the new study, researchers harvested immune T cells from a single donor, a healthy 21-year-old woman. They reprogrammed the donated cells with a single gene that addressed the overzealous B cells behind two autoimmune diseases.
The first, immune-mediated necrotizing myopathy (IMNM), attacks the muscles and is generally not treatable with drugs. The other, systemic sclerosis, is particularly nasty because it damages internal organs and leaves irreversible scarring around the heart and kidneys.
The team used the gene editor CRISPR-Cas9 to remove five genes from donor T cells, preventing them from attacking host cells and protecting them from the host’s immune system. These cells are also designed to attack dangerous B cells that trigger autoimmune responses.
The study recruited three people aged 42 to 56 years, two with systemic sclerosis and one with IMNM. After infusion, CAR T cells proliferated and destroyed target B cells. Most engineered cells survived for several weeks in the body and then shrunk. This is a common phenomenon with this type of treatment.
But it worked.
IMNM patients’ symptoms completely disappeared after 2 months of treatment, and they remained symptom-free for at least 6 months. She regained use of her muscles and reported a better quality of life. Magnetic resonance imaging (MRI) of the thigh muscles showed a decrease in swelling and inflammation.
Over time, her B cells returned to normal levels. However, rather than causing disease, the cells were healthy and fought pathogens instead of attacking their own bodies.
Two other people with systemic sclerosis also saw improvements. Their symptoms steadily improved over two months after treatment, and the symptoms persisted for at least half a year. The engineered cells rejuvenated damaged skin and lung tissue and restored them to younger, healthier versions.
In all three people, antibodies that attack healthy tissue dropped to almost undetectable levels.
“The clinical results are surprising,” said Dr. Lin Xin of Tsinghua University, who was not involved in the study. nature.
the way forward
Although promising, the study is very small. The research team plans to further test the treatment on about 15 people with autoimmune diseases.
However, the safety profile was maintained. One concern with CAR T therapy is a runaway immune response called a “cytokine storm.” Here, the body uses large amounts of immune molecules to attack CAR T invaders, damaging healthy tissue. In all three participants, the engineered cells performed as expected with minimal side effects.
Cancer is another concern. A small number of cancer patients who received engineered cells developed new tumors months to years after treatment. Whether the cancer is caused by CAR T cells is still up for debate, but the team knows the risks.
They will follow three patients to measure treatment effectiveness and safety and recruit more patients for the clinical trial.
Eventually, researchers want to compare off-the-shelf CAR T cells with individually engineered cells in terms of how well they work and how much they cost. Developing universal rather than personalized treatments could lead to the next generation of affordable, adaptable, and safe “living drugs” that can curb autoimmune diseases.
Image credit: NIH via Flickr
