CAR T-cell therapy is a type of immunotherapy first approved in 2017 by the U.S. Food and Drug Administration (FDA) as a treatment for patients younger than 25 with a form of acute lymphoblastic leukemia, a blood cancer. “CAR” stands for chimeric antigen receptor, a special type of receptor that gets added to a patient’s T cells (which are part of the immune system) in the lab and makes those T cells attach to cancerous cells and kill them (according to the National Cancer Institute’s definition). CAR T-cell therapy has also been approved for adult patients with aggressive non-Hodgkin lymphoma that have relapsed or failed on other therapies. RELATED: FDA Approves CAR T-Cell Therapy for Some Cases of B-Cell Lymphoma Researchers have now successfully used this same type of therapy to treat mice with lupus. When the mice were injected with CAR T cells, the therapy killed off B cells, which play a key role in lupus. The data, published on March 6 in Science Translational Medicine, found that the mice with lupus who were treated with CAR T cells lived longer and had healthier spleens, kidneys, and skin (organs typically affected by lupus) than the mice in the control group who did not receive the treatment. RELATED: What Causes Lupus? According to the Lupus Foundation of America there are approximately 1.5 million people in the United States with lupus and another 3.5 million people with the disease elsewhere. In healthy people, the body produces antibodies to fight off foreign invaders, such as viruses, bacteria, and fungi, that compromise health. The antibodies in a person who has lupus can’t distinguish between the invaders and the body’s own cells and tissues, so the antibodies the immune system produces attack healthy tissue. This can cause arthritis, lupus rash, kidney damage, and other health problems. RELATED: The Common Signs and Symptoms of Lupus “Immunotherapy with CAR T cells has shown impressive efficacy in hematological malignancies, and this is a first attempt to treat a systemic autoimmune disease like lupus with the same approach,” says George Stojan, MD, an assistant professor of medicine at the Johns Hopkins Lupus Center in Baltimore, who was not involved in this research. The new approach seems promising, he says.
CAR T-Cell Therapies Are Engineered to Attack B Cells, Which Play a Role in Lupus
T cells are white blood cells that develop in the thymus gland and are known as the “attack” arm of the immune system, the troops sent out to defend our bodies against those foreign bacteria, viruses, and fungi that might invade. Cancer cells have a variety of ways to avoid detection and can still elude these highly specialized defender cells. That’s where CAR T-cell therapy comes in. Special T cells (that have been taken from a patient and re-engineered in a lab) are better at recognizing and killing certain kinds of cancer, such as B-cell leukemia and B-cell lymphoma. Research shows that B cells also have a key role in how and why lupus progresses. The antibodies produced by B cells in people with lupus lead other immune cells to attack various healthy tissues in the body. “We envisioned this study as a way to test to see whether eliminating or depleting B cells would also lead to an improvement in lupus and in the symptoms of the disease,” says Marko Radic, PhD, an associate professor at the University of Tennessee Health Science Center in Memphis and the lead author of the study. Radic and his team used CAR T-cell therapy to target CD19 B cells. “CD19 is actually the same target as was used in the treatment of leukemia and lymphoma patients, and we went after the same target in these mice,” says Dr. Radic. Radic and his colleagues injected the genetically engineered T cells into 41 mice to see if they were effective in killing the B cells. The results showed that in 26 mice, the CAR T cells killed all B cells displaying CD19 (the ones that seem to play a role in lupus) and that all signs of lupus had been removed from the spleen, kidneys, skin, and other organs of the mice. “Not only were the CD19 B cells almost completely absent from the blood and tissues of these mice [after the mice had been treated with the CAR T-cell therapy], the production of autoantibodies returned to unmeasurable levels, too,” says Radic. “It was also impressive that the mice lived a year after the treatment,” says Radic — particularly considering that if a similar effect could be replicated in humans, that would translate to a longer period of time.
There Are Still Questions to Answer Before CAR T-Cell Therapy Can Be Used in People
It is unclear if the success in treating lupus by CAR T-cell therapy will be duplicated in humans. (Remember this new trial was done in a lab on mice.) “The next steps should be exploring its efficacy and safety in clinical trials for lupus,” Radic says. The study authors aren’t certain why killing off the B cells with CAR T-cell therapy might have better results than other immunotherapy drugs that are designed to do the same thing, but have failed. An encouraging finding from this new study was that the modified T-cells were still active in the mouse models, suggesting that they might be more durable than other immunotherapies. Right now, a big question is whether, if the CAR T-cell therapy is successful and all B cells are eradicated, people are left with very low serum immunoglobin levels, which would make them much more vulnerable to dangerous infections, Dr. Stojan notes. There is also the risk of cytokine release syndrome, a common side effect of using CAR T-cell therapy, which can be life-threatening, Stojan says. It happens as a side effect of the immune system’s getting activated (by the drugs), he explains. “It manifests with high fever, rapid heart rate, low blood pressure, capillary leak, cardiac dysfunction, renal impairment, hepatic failure, and disseminated intravascular coagulation.” Other potential side effects for the drug include: confusion, delirium, myoclonus (involuntary muscle jerks), seizures, and aphasia, Stojan adds. The risk of all these potential side effects — particularly for cytokine release syndrome — is why clinical trials have strict rules about which patients can join. “Currently, CD19 CAR T-cell trials recruit patients with no evidence of organ dysfunction, normal blood counts, normal ECG, normal renal function, no liver function abnormality, no coagulation abnormality, etc.,” Stojan says. It would be challenging to find a lupus patient with active disease who would meet all the inclusion criteria for a trial like this, he says. Many health issues that come with active lupus patients would make treatment with the current version of CAR T-cell therapy difficult. “Considering where CD19 CAR T-cell therapy is at this point in time, I can only see it used in a very small proportion of lupus patients,” he says. Even though the findings from this study will not change the approach to treatment of lupus in the near future, it will open up new avenues for research going forward, Stojan adds.
