CAR-T Cell Therapy and Lupus

While a rare and expensive treatment, CAR-T cell therapy enables drug-free remission by using the immune system itself to clear out the cells that cause autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disease that turns the body’s own immune system against itself. So, it shouldn’t seem too out-of-the-blue that many treatments for SLE target the immune system. Usually, these medications reduce inflammation, or by forcing the immune system to be less active. These medications have serious and unpleasant side effects, but for many people with lupus, reducing or even stopping their lupus symptoms is worth it. You can read more about lupus medications here. 

However, other therapies try to actually make the immune system work the way it’s supposed to.

CAR-T cell therapy is a type of therapy called “immunotherapy” which uses the body’s own immune system to treat patients. CAR – T therapy takes T-cells already produced by the body and modifies them. After being modified, the patient’s own immune system is better able to target and attack cancerous cells but there are a lot of potential benefits for people with autoimmune diseases. In fact, a recent study demonstrated that CAR-T cell therapy can suppress lupus symptoms into what is known as remission – without compromising the patient’s immune system!

What is Remission?

Remission in lupus is the long-term lack of symptoms or flares after treatment. Some people with well-managed lupus were able to go for up to 5 years, or even longer, without dealing with symptoms or flares. Usually, this is achieved with lupus medications, including immunosuppressants, taken over many years. Over time, these medications control inflammation in the body to a point where it can heal some of the damage and stop the rampaging symptoms of lupus, but they don’t cure it. Lupus is always there and can be triggered back into the disease later on.

There are several often-frustrating side effects to lupus medications, and one of them is that a suppressed immune system is more vulnerable to sickness and infection. When someone has a compromised and vulnerable immune system, it is known as being immunocompromised. It is also harder for a vaccine to ‘take’ in people who are immunocompromised – there just is less of an immune system for the vaccine to train. Because of this, researchers have been looking into treatment methods that can allow people with lupus to achieve remission without weakening their immune systems. Not everyone responds to typical lupus treatments either, a situation known as refractory lupus – they need alternative therapies. You can read more about refractory lupus here. CAR-T cell therapy is one such therapy under investigation.

What is CAR-T Therapy?

There are several different types of CAR – T therapies, but overall, CAR stands for “Chimeric Antigen Receptor.” Receptors are structures on cells that allow them to “receive” certain molecular structures on their surface. Each receptor only matches with a limited number of molecules that fit its shape. Once a receptor attaches to its matching molecule, or a closely related one, a switch is flipped in the cell, starting a chain reaction throughout the cell that allows it to respond. This is how cells throughout the body work, and in the case of an antigen receptor, immune system cells like T-cells use these receptors to sniff out pathogens and activate the correct response. With CAR, these antigen receptors are laboratory engineered structures that better recognize B cells.  Equipped with these upgraded receptors, T Cells are able to sniff out and destroy B cells.

B-Cells and Lupus

B cells, also known as b-lymphocytes, are a type of immune system cell that attacks viruses, bacteria, parasites, and cancer – anything that uses the body’s own cells to hide or reproduce. These cells usually detect special antigens that stressed or damaged cells produce and will attach to those antigens and trigger a self-destruct mechanism in the cell. However, in autoimmune disease, these cells ‘sniff out’ healthy cells too, attacking them. Not only does this cause damage to those cells and to the organs that use those cells, but the defective B cells signal to the body that there is a threat, leading to inflammation, or higher levels of immune system activity. Over time, the damage accumulates, and the body becomes more trained to attack these cells, leading to a vicious cycle of autoimmunity. In addition to also killing off sick cells, T cells are one of the ways that the body culls out the B cells that target healthy cells, but for yet unknown reasons, the T-Cells aren’t doing their jobs properly in people with autoimmune diseases such as lupus. CAR-T therapy puts T cells back on the job, reducing the amount of B cells in the body that can cause problems for a patient. You can read more about T Cells and their functions here. 

Because it improves the function of the immune system – working with what is already there without involving other organs – serious side effects are rare.

Chimeric? What does that mean?

“Chimeric” means that the CAR antigens were developed using the genetics of multiple species to get the receptor structure they were looking for. Since all life forms on the planet use the same general source code, DNA (or RNA for viruses,) the body has no issue using or replicating the new antigens. 

Several of the side effects of CAR tend to be reactions to the infusion process itself. CAR – T therapy is usually given intravenously as an infusion, and the white blood cells modified as part of the therapy are drawn from the patient’s own bloodstream.

Unfortunately, the body doesn’t always respond well to needles, having blood drawn, or having medication flowing directly into the bloodstream. Sometimes the body will go into a stressed state known as vasovagal synope. Essentially, the body panics, thinks that you are wounded, and lowers the heartbeat and breathing rate. This leads to a sudden drop in blood pressure and feelings of lightheadedness. Nausea, fever, fatigue, loose stools, and confusion can result as the body overreacts. A person can even fall unconscious for a short time. While vasovagal synope usually goes away on its own, it’s something that should be looked into further if it’s common. 

This is not a reaction to the antigens themselves, but the process of administering the medication. Since the cells come from the person’s own body, rejection or allergic reaction is unlikely.

The Research on CAR-T Cell Therapy

In the study, presented at the American College of Rheumatology’s annual meeting in 2023,  8 patients with lupus were treated with CAR-T therapy, 5 of which had follow ups a year or more post-CAR T therapy. All of these patients were able to achieve drug-free remission on this therapy, for 8 months or more. They were not taking immunosuppressants, and tested negative for autoantibodies – antibodies that marked the body’s own cells. Their immune systems were left intact and relatively robust, and the patients were able to be successfully vaccinated for measles, mumps, rubella, varicella zoster virus, Epstein-Barr, tetanus, and pneumococcus. This is because, after the autoimmune B cells were cleared from their system, they produced fresh, new B cells. 

These cells did not immediately attack the body, and instead behaved as normal and were able to be trained to the vaccines. This does not happen under immunosuppressants, so this was an exciting find. Patients tested negative for autoantibodies and remained in remission until the end of the study. 

Of course, this study was done on 5 people – a tiny sample size. None of them were of African descent, and only one was registered as Hispanic, which is not representative of the population. There are also side effects and cost limitations to CAR-T treatment, and it is not approved for lupus patients in the US. However, it is approved for several cancer treatments, which makes this study extremely promising. It is also not the only study of its kind:

In a 2020 study on 43 patients, the researchers saw 51% of their patients go into remission for more than 3 years after the therapy. Some of the patients had remissions as long as 9 years (and still going) by 2020. They noted few adverse effects from the treatment, as well. 

Side Effects of CAR-T

Aside from the effects of the infusions and blood draw, CAR-T has a few other notable side effects. In addition to potential allergic reactions, the depletion of certain vital minerals and cells in the bloodstream, and a weakening of the immune system as the T Cells clear out the B cells. 

Cytokine Release Syndrome

Cytokine release syndrome (CRS) also known as a “Cytokine Storm” CAR-T cells are modified, but living, cells and can replicate themselves in the body. As they begin to target B cells, they release cytokines into the blood stream. Cytokines are proteins made by the body to act as messengers, helping the immune system coordinate itself and the rest of the body into combatting a threat. Or, in some cases, sounding the all-clear. Cytokines have many functions, but the sudden rush of cytokines caused by the modified T cells can overwhelm the body, suddenly ramp up inflammation, and even potentially be life threatening. The symptoms of a cytokine storm are very similar to a flu, and this is because the cause is similar – the immune system is pushed into hyperactivity by a storm of cytokines. However, without a threat like the flu, the body is making itself sick for no benefit.

While possible, the cytokine storm complication of CAR-T seems to be uncommon. 

Nervous System Symptoms

It’s not clear why CAR-T can have several serious effects on the immune system, but it can cause:

• Headaches
• Unconsciousness
• confusion
• seizure
• tremors
• loss of balance
• trouble speaking and understanding language.

These seem to be temporary, however, and doctors only advise against avoiding dangerous activities and using heavy machinery for several weeks after the therapy.

In addition, while CAR-T seems to cause long-lasting remission, relapse is also still possible after the therapy, so it shouldn’t be thought of as a cure – like any other treatment for lupus.