Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a spectrum of very different manifestations and variable severity.
This makes the condition difficult to diagnose and treat, aiming to put the disease into remission rather than cure it.
The most common symptoms of lupus are joint pains and swelling, as well as several types of rashes, the most typical being in a “butterfly” pattern over the cheeks and nose, or dark, circular, scaly “discoid” lesions. More significant organ inflammation can also occur, particularly in the kidneys, which can result in the need for dialysis or transplant.
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However, many other symptoms can be more subtle and not everyone with lupus has the same symptoms, leading to the condition’s reputation as a cruel mystery due to its significant effect on quality of life and often hard-to-diagnose nature.
Recently, testing of treatments known as cellular therapies, often called “CAR-T,” has shown promise beyond the medications traditionally used to treat lupus, leading many to wonder if a cure for this disease may be possible.
Early phase clinical trials are currently underway to determine the safety and efficacy of this therapy in SLE, with early reports of patients responding exceptionally well.
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How Is CAR-T Used In Lupus?
Cellular therapies have already been approved and are being used in the treatment of several types of cancers. In the most common therapies, blood is taken from a patient, and a type of immune cell called T cells is isolated from their own blood and genetically modified to target cancer cells.
These modified cells are then infused back into the patient after receiving doses of chemotherapy, which act to stimulate the CAR-T cells to expand and destroy cancer cells.
In lupus, the CAR-T cells are modified not to target cancer, but instead a different type of immune cell called the B cell. The inflammation in SLE is caused by the immune system being overactive and attacking the body. B cells play a major role in this, leading to the creation of antibodies that damage healthy tissue.
There have been several successful lupus medications that target “B” cells, but cellular therapies deplete these cells more completely throughout the body.
How CAR-T Is Being Tested in Lupus Patients
Several ongoing trials are evaluating cellular therapies in lupus patients. These early-phase trials include people who have more severe presentations of the disease and have failed multiple prior treatments.
Most trials include patients with kidney disease, while some also include other manifestations such as debilitating arthritis or rashes that affect patients’ day-to-day life. Because this is a new treatment in lupus and most current CAR-T protocols include chemotherapy that may have significant side effects, the initial trials are limited to those who are very sick and for whom the benefits would outweigh the potential risks.
Most current CAR-T clinical trials are in phase 1, in which the primary objective is assessing the safety of an experimental treatment, although the therapy’s effectiveness is also studied.
In these studies, the first few patients will get a certain dose, be monitored for side effects and undergo blood tests to identify how the body and the treatment interact. If no significant issues arise, higher doses may be studied until an ideal dose is settled on.
In phase 2 and phase 3 trials, more patients are studied, and while evaluating safety remains important, how well the treatment works becomes the primary outcome. If a drug has a positive phase 3 study, it is often approved by the U.S. Food and Drug Administration (FDA) for use.
Many CAR-T therapies have been fast-tracked by the FDA to speed up development, but it typically still takes years before these therapies are available to everyone. Until then, patients who meet criteria for clinical trials may be able to enroll at one of several major academic centers that are clinical sites, such as NYU Langone Health.
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What are some of the initial findings so far for patients undergoing Phase 1 trials?
We are seeing unprecedented results. Physicians who treat lupus have traditionally hesitated to use the word “cure” in the past because even with our most effective treatments, patients can flare, and long-term use of at least some medication is usually required.
With cellular therapies, we are seeing significant responses with quick resolution of both clinical and laboratory abnormalities, including in patients with organ manifestations such as kidney disease.
Most significantly, when we look at the actual makeup of the immune cells after CAR-T therapy, we see B cells coming back after chemotherapy as “naïve” – they no longer attack healthy tissue anymore.
It is likely for this reason that patients receiving these treatments not only have improved symptoms and lab results, but also have been able to stop their other lupus medications.
What should patients expect when getting CAR-T treatment for lupus? What are the steps?
Each company studying cellular therapies has its own methods for conducting trials. All require patients to undergo an initial screening to evaluate their lupus activity based on clinical and laboratory measures and to document their treatment history.
If the screening criteria are met, patients typically begin to discontinue their medications in preparation for leukapheresis.
This is the procedure in which blood is drawn to harvest the T-cells for genetic modification. From there, it takes a few weeks to create a patient’s personalized treatment, using their own blood.
The next phase is chemotherapy, which will wipe out the immune system and will prepare the body for the expansion of CAR-T cells, a process called lymphodepletion. Afterwards, the patient is usually hospitalized for one to two weeks to receive the one-shot CAR-T infusion and be monitored closely as the therapy begins to take effect.
While the cells need to expand in order to target the B cells and destroy them, this process can create a large inflammatory response. This can lead to significant side effects, including fever, low blood pressure and neurologic symptoms such as mild confusion and headaches, to severe issues like seizures, coma, or swelling in the brain.
These issues can be treated, but close monitoring is required. The healthcare team also needs to watch for infections as patients’ immune systems have been suppressed by CAR-T therapy and chemotherapy.
Once patients are able to go home, we can see them every couple of weeks to monitor their progress.
Patients will start to see their immune system reconstitute after several months and their risk of infections will decrease. They will be monitored for many years, given that this is a new form of treatment for lupus.
Doctors will determine if these treatments have sustained responses or if additional rounds of treatment are feasible, safe and effective.
About the expert
Dr. Amit Saxena is an associate professor of medicine at NYU Grossman School of Medicine in the division of rheumatology. He specializes in autoimmune diseases, with a focus on systemic lupus erythematosus (SLE) and neonatal lupus. His research bridges lab science and patient care, and he leads clinical trials aimed at improving outcomes for people living with lupus.
