CAR-T Cell Therapy For Lupus Made Simple (October 2024 UPDATE)

posted in Drugs used in lupus on January 6, 2024 by

Donald Thomas, MD

Updated October 25, 2024

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The field of CAR-T therapies in treating autoimmune diseases like lupus is rapidly expanding. As of April 2024, at least 43 patients with severe systemic lupus erythematosus (SLE) had been treated with CAR-T cell therapy. Most went into drug-free remission, meaning they were completely off their lupus medications (like prednisone, hydroxychloroquine, methotrexate, mycophenolate, etc). There were very few major side effects.

4/27/24 Update

An “off-the shelf” version of CD-19 CAR-T is now recruiting SLE patients (Nebraska/Minnesota)

4/11/24 Update:

It appears that the number of patients being treated with CAR-T is accelerating (this up date is up to 43 SLE patients treated with CAR-T). From this point onwards, I’m sure I won’t be able to include all study releases. However, if you know of any that I miss, please reply in the comments with a link to the study so that I can include that data. 

Several sites are now recruiting for SLE patients, see below. 

In addition to SLE, I will discuss these autoimmune diseases that have been treated with CAR-T

– Sjogren’s disease

– rheumatoid arthritis

– systemic sclerosis (scleroderma)

– myositis

– myasthenia gravis

– neuromyelitis optica

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NOTE TO READERS: CAR-T cell therapy for autoimmune diseases is a rapidly growing field. If you know of any studies I am missing, please let me know in the comments

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3/24/24 Update:

• At least 43 SLE patients had been treated as of March 2024
• Update on the 15 German autoimmune disease patients
• Novartis reports success in 6 SLE patients
• Two pediatric lupus nephritis patients treated with CAR-T
• Two SLE patients with lupus nephritis treated with Kyverna’s KYU-101
• 12 patients with neuromyelitis optica do well with BCMA
• Two Sjogren’s disease patients and one rheumatoid arthritis patient responded well to CAR-T cell therapy

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1/17/24 Update: CAR-T lymphomas seen after some CAR-T cell therapies. Discussed below (click on the highlighted link above)

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Is CAR-T a miracle cure for lupus? Is this the future and the start of a new era?

From 2021 to 2023, doctors at the Friedrich-Alexander University, Erlangen-Nürnberg, Erlangen, Germany, described 8 patients with treatment-resistant severe systemic lupus erythematosus who went into remission using a treatment called CAR-T cell therapy. The CAR-T treatment was safe, caused no major side effects, and all the patients stayed in remission without additional ongoing medications or immunosuppressants. CAR-T therapy has kept the initially treated patient in remission for over 3 years. The data of her long-lasting remission was presented at the 2024 EULAR meeting in Vienna, Austria, in June 2024. Two SLE patients in China are still in remission after CAR-T cell therapy treatment over 3 1/2 years ago.

Since then, CAR-T cells have been a hot topic among patients with autoimmune diseases and rheumatologists. However, most people do not precisely understand CAR-T cells.

The purpose of this blog post is to simplify the concept of CAR-T cells.

I’ll start with a much-simplified explanation. I recommend that you read at least this initial short, easy-to-understand section.

I’ll then take a simplified deep dive into the science of CAR-T cell therapy for lupus.

I’ll talk about CAR-T therapy’s pros, cons, and future.

Then, I’ll list the clinical trials that are going on as of April 2024 (the number of research studies continues to grow since then). The number of new clinical trials is rapidly increasing. If you know of any new ones I have not included, please let me know in the Comments section (click on “Leave a Comment” top right of this page).

Doctors can refer patients to some of these for CAR-T therapy for lupus. I have included the contact information as well.

What are CAR-T cells?

CAR-T cells are specially engineered T-cells (a type of white blood cell) infused into the patient. These CAR-T cells identify B-cells (a type of white blood cell described below) in the patient’s body to attack and destroy those B-cells.

This is important in lupus because the B-cells make the antibodies (called autoantibodies, like anti-dsDNA) that attack and destroy the patient’s body organs. Destroying these “bad” B-cells (scientifically called “autoreactive B-cells”) results in the disappearance of these organ-destroying antibodies.

CAR-T cells is short for “chimeric antigen receptor T-cells.” We can break this down into four parts (chimeric, T-cells, and the antigen receptor that is produced by virus-inserted DNA):

Chimeric means something that is made up of different organisms. The chimera was a Greek monster that was part lion, goat, and snake.

CAR-T cells explained

The Patient’s T-cells

T cells (① in the diagram below) come from the patient themselves. These T-cells from the patients are the primary sources of the live CAR-T cells.

An antigen receptor (③) is produced by genes (②) that a virus inserts into the inner nucleus of the T-cell.

Therefore, a chimeric antigen receptor T-cell (CAR-T) is made of the cells originally from the patient but also has foreign genetic DNA introduced by a virus. This foreign DNA produces “antigen receptors” that become inserted in the T cells’ outer membranes.

The Antigen Receptors

Antigen receptors (③ in the diagram above) are produced by virus-inserted DNA and inserted into the T-cell’s outer membrane.

The antigen receptor has two main sections: an outer section outside the cell and an inner section inside the cell. The antigen receptor’s outer section (sticking outside of the CAR-T cell) can identify and attach to antigens.

Think of an “antigen” as an identification badge. In this case, the antigens are molecules found on B-cell surfaces. The antigen used in the 8 SLE patients described above was CD-19, which is only found on mature B-cells (but not on plasma cells). The CD-19 antigen identifies that cell as a B-cell, not any other type (like a T-cell, muscle cell, or red blood cell).

The antigen receptor’s outer section identifies and attaches to other cell’s antigens (on the outer membrane of that other cell, in this case, B-cells). This attachment to the other cell’s antigen signals the antigen receptor’s inner portion to tell the T-cell to destroy the cell (B-cell) it is attached to.

B-Cells and Lupus

B-cells are white blood cells of the immune system that make the dangerous autoantibodies of lupus. For example, the B-cells of many lupus patients make an autoantibody called “anti-dsDNA.” “Auto-“ comes from the Greek word for “self.” Autoantibodies are immune system molecules that attack the person itself. B-cells that make lupus autoantibodies that attack the person’s own self are called “autoreactive B-cells.”

I’ll simplify this in this article and call autoreactive B-cells “bad B-cells.”

Autoantibodies (like anti-dsDNA) can go to the organs (like the kidneys) causing inflammation, damage, and even organ destruction. When they attack the kidneys, this is called lupus nephritis. Destroying these “bad” B-cells could potentially help decrease this inflammation and damage.

The antigen receptors on the CAR-T cells identify the patient’s B-cells and attach to the B-cells. This activates the part of the antigen receptor inside the CAR-T cell, which tells the CAR-T cell to destroy the B-cell that it is attached to.

The CAR-T cells are finally produced for lupus patients

Laboratory technicians finally produce the CAR-T cells in a laboratory by infecting the patient’s T-cells (① in the diagram above) with virus that are designed to insert DNA (② in the diagram above) inside the T-cells’ nucleus. This DNA tells the patient’s T-cells to produce the antigen receptors (③ in the diagram above) described above and insert the antigen receptors into the CAR-T cell’s outer membranes.

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Summary: CAR-T cells are

① T-cells that originally came from the patient being treated

② and contain virus-inserted DNA

③ that causes the production of antigen receptors on the CAR-T cell’s outer cellular membrane

④ the antigen receptors recognize and attach to B-cells so that the CAR-T cells destroy B-cells.

What is the CAR-T cell therapy process for lupus patients?

Above is a simplified explanation of CAR-T cell therapy used for lupus patients. Now, let’s have a more detailed look.

NOTE: This description is for DNA-based CAR-T cell therapies, which have been used in most patients reported on thus far. RNA-based therapies (such as Cartesian’s Descartes-08) do not involve some steps (such as using cyclophosphamide and fludarabine, and the CAR-T cells do not reproduce after being infused back inside the patient’s body).

Apheresis removes T-cells from the patient

First, the patient has blood removed by a procedure called apheresis (as in the photo below).

An apheresis machine (shown below) separates white blood cells (that contain the needed T-cells to turn into CAR-T cells) from red blood cells and other blood particles.

Technicians produce special DNA-inserting virus from lentivirus

Laboratories specially design a type of virus, called lentiviruses, to infect T-cells and insert DNA that makes the needed antigen receptors.

What are lentiviruses?

Lentiviruses exist in nature. They are dangerous and can be deadly. Lentiviruses especially like to infect white blood cells (like T-cells). They insert RNA (ribonucleic acid) and essential enzymes to produce DNA into the infected person’s cells. This RNA and the needed enzymes make virus DNA that it inserts into the DNA of the infected cell. This foreign, viral DNA forces the infected cell to manufacture much more lentivirus. This is how the virus reproduces itself. In the process, the cell can die. The newly constructed lentivirus particles can then infect more T-cells in the person, making them sick.

Using lentiviruses for medical treatments

Since lentivirus can insert DNA into the DNA of other cells, it is a perfect vehicle for reproducing anything that can be made from DNA (such as parts of a CAR-T cell).

For example, betibeglogene autotemcel (Zynteglo) is a gene therapy where specially engineered lentivirus inserts genes into patients’ bone marrow cells, causing them to produce healthier red blood cells. Doctors use Zynteglo to treat patients with a severe form of anemia called beta-thalassemia.

Lentivirus use in CAR-T cell therapy

For CAR-T cell production, technicians produce specially engineered lentiviruses in a laboratory. These lentiviruses do not contain their original dangerous virus-producing RNA. Instead, unique DNA (see image below) is engineered to make the needed antigen receptors for CAR-T cells. These unique DNA are placed inside lentivirus that do not infect and kill people. Instead, the engineered lentivirus can infect T-cells from a person’s body and insert this CAR-T-producing DNA.

Lentivirus inserts antigen receptor-producing DNA into the patient’s T-cells

Technicians take the white blood cells from the apheresis machine and remove as many T-cells as possible from the blood cells. In a sterile (germ-free) laboratory, these T-cells are infected with the specially engineered lentivirus DNA (or mRNA for other brands of CAR-T cells) that can tell the T-cell to produce specific antigen receptors (see image below).

The virus inserts this DNA or mRNA into the T-cells (see image below).

The patient’s T-cells produce the antigen receptors: A CAR-T cell is born!

The T-cells then produce the CD-19 (or BCMA, or both, but also other types are possible) antigen receptors and insert them into their outer cellular membranes (see image below). At this point, they are called CAR-T cells.

The CAR-T cells are replicated (multiply) in the laboratory

The technicians stimulate these CAR-T cells to reproduce and produce large numbers of CAR-T cells.

Chemotherapy removes T-cells (lymphodepletion) from the patient prior to CAR-T cell infusion

The patient is treated with two chemotherapy drugs: cyclophosphamide and fludarabine. These drugs cause the person’s white blood cells, especially the T-cells (called lymphodepletion), to drop significantly in number.

Note that some CAR-T cell therapies do not require chemotherapy lymphodepletion (such as Cartesian’s Descartes-08, using mRNA instead of lentivirus DNA).

Healthcare professionals infuse the CAR-T cells into the patient

The patient, who now has very few T-cells after receiving chemotherapy, is infused with the CAR-T cells produced in the lab.

The CAR-T cells multiply (replicate) inside the patient

The person’s immune system senses the loss of T-cells after the previous chemotherapy. As a natural response to this lack of T-cells, the infused CAR-T cells reproduce rapidly, trying to replace the lost numbers of T-cells in the body’s fluids and organs. This step can potentially cause side effects, like complement activation syndrome, described below.

This step occurs with CAR-T cells that are DNA-based (as in the initial 8 patients described above). CAR-T cells that are RNA-based, like Cartesian’s Descartes-08, do not multiply inside the body. This is important as there have been rare cases of DNA-based CAR-T cells resulting in CAR-T cell lymphoma (discussed below). CAR-T cell lymphomas should not occur with RNA-based CAR-T cell therapy since they do not multiply in the persons’ body.

The CAR-T cells destroy the patient’s B-cells 

The CAR-T cells identify the designated antigen (in the case of the SLE patients above, this is CD-19; see image below).

After identifying and attaching to the target antigen and cell (B-cells with CD-19 antigens on their surface), the antigen receptor activates the CAR-T cell to go into “kill mode.” (see diagram below).

The CAR-T cell then destroys the B-cell (as per the image below). Most importantly, the CAR-T cells also destroy the “bad” B-cells that produce dangerous lupus autoantibodies (like anti-dsDNA, anti-SSA, and anti-chromatin antibodies). These dangerous antibodies disappear and stop attacking organs in the lupus patient.

Why do CAR-T cells work better than other B-cell-depleting drugs?

Some other lupus treatments also decrease the number of B-cells (B-cell-depleting drugs). The most commonly used B-cell-depleting drugs are rituximab (Rituxan) and belimumab (Benlysta). Others, like obinutuzumab (Gazyva), also look promising. These are monoclonal antibodies produced by biological methods (i.e., biological drugs). Antibodies are also “antigen receptors,” just as in the CAR-T cells. However, they have a different structure. “Monoclonal” means that these antibody drugs are all the same type. Mono– clonal means one-clone or one-type.

They differ in which antigens they recognize. The rituximab and obinutuzumab monoclonal antibodies (also antigen receptors) recognize an antigen molecule called CD-20 found on the surface of B-cells and some T-cells. When rituximab or obinutuzumab attach to CD-20 on B-cells and some T-cells, this interaction alerts the immune system, destroying the B-cell.

The belimumab (Benlysta) monoclonal antibody (again, a type of antigen receptor) binds to an antigen called soluble B lymphocyte stimulator protein (BLyS). B-cells rely on BlyS to mature into cells that produce the dangerous lupus autoantibodies (like anti-dsDNA). However, when belimumab binds to BlyS, the BlyS molecules cannot bind to the B-cells. Therefore, the B-cells cannot mature, and their amounts decrease, reducing autoantibody production.

“Bad” autoreactive B-cells hide from B-cell-depleting drugs

Although these drugs work in many lupus patients, they do not help many others. One probable reason is that these drugs cannot reduce all B-cells in the body. These monoclonal antibody drugs are present in the body’s fluids (blood and lymph) and work on the B-cells in these fluids. However, there are a large number of B-cells producing dangerous lupus autoantibodies in the tissues of the body where these monoclonal antibodies are unable to reach. For example, research studies show that B-cells continue to reside in the joints, lymph nodes, and tonsils after treatment with these agents.

CAR-T cells find and destroy all B-cells

One advantage of CAR-T cells is that they easily penetrate the tissues (like the joints and lymph nodes), where they can attack those B-cells unaffected by belimumab, rituximab, and obinutuzumab. The B-cell destruction is complete. This differs from monoclonal antibody therapies (rituximab, belimumab, obinutuzumab), where dangerous, “bad” B-cells still exist in the body’s tissues.

Rituximab and obinutuzumab target CD-20 antigens on the cell surface of B-cells and some T-cells. One problem with this is that a type of mature B-cell called plasmablasts does not have CD-20 antigens, and they persist after rituximab treatment. Plasmablasts produce dangerous autoantibodies, like anti-dsDNA, and are increased during lupus flares in rituximab-treated patients. CAR-T cells destroy these plasmablasts (a type of mature B-cell).

Another disadvantage of monoclonal antibody drugs (like rituximab and belimumab) is that patients must continuously use them. When stopped, the “bad” B-cells that produce the dangerous autoantibodies increase again.

Side effects of CAR-T cell therapy for lupus

Fortunately, CAR-T cell therapy in patients with lupus caused few major side effects in the published medical studies (as of October 2024).

This is not what happens in patients with cancer treated with CAR-T cells. Blood cell cancers, where the B-cells become cancerous, have been the primary use for CAR-T cell therapy. Several FDA-approved CAR-T treatments are available to treat B-cell leukemia and multiple myeloma (a cancer of plasma cells, which are mature B-cells). In these studies, some severe side effects and even deaths occurred.

We must consider these possible side effects when treating autoimmune diseases. However, there are some significant differences between B-cell cancers and autoimmune diseases.

One of the most important is the number of B-cells killed by the CAR-T cells. Much lower numbers of B-cells are destroyed in autoimmune disease patients. However, huge numbers of B-cells are destroyed in people who have B-cell cancers and multiple myeloma. For example, in the first few weeks of CAR-T cell therapy for B-cell cancer, a few pounds worth of B-cells can be destroyed. This large number of B-cell deaths could be a reason for some of the severe side effects seen when CAR-T is used in cancer patients, yet not seen in patients with autoimmune disease.

Cytokine release syndrome (CRS)

One side effect is called “cytokine release syndrome” (CRS). You may remember hearing this term during the COVID-19 pandemic. It was also called “cytokine storm.” COVID-19 infection could cause CRS and was a common reason for deaths. CRS is a condition where the immune system becomes overactive, attacks the person’s organs, and can lead to death. Common symptoms of CRS include fever, body pains, headaches, lightheadedness, and drops in blood pressure.

The same thing can happen with CAR-T therapy for B-cell cancers. Some immune system molecules (like IL-6) are exceptionally high during CRS. Tocilizumab (Actemra) inhibits the activity of IL-6 and is FDA-approved to treat some autoimmune diseases, like rheumatoid arthritis. Also, it effectively treats CRS caused by CAR-T therapy and COVID-19. Steroids are also used to treat CRS. Using tocilizumab and steroids, most people survive CRS.

Most autoimmune disease patients have developed CRS. Fortunately, no severe, untreatable CRS occurred in any SLE patients. So far, it has been a manageable side effect.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Immune effector cell-associated neurotoxicity syndrome (ICANS) is another dreaded side effect of CAR-T therapy. ICANS affects the brain and nerve cells, potentially causing permanent damage if severe. Common symptoms of ICANS include headaches, tremors, tingling sensations, coordination problems, and moodiness. More severe complications include muscle weakness, numbness, trouble speaking and writing, confusion, hallucinations, seizures, coma, and even death. Major risk factors for developing ICANS are having a high number of B-cell cancer cells and if the person had had any previous neurologic problems.

As of October 2024, ICANS has not been seen in SLE patients treated with CAR-T (in the studies that I am aware of).

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CAR-T Cell Lymphoma after CAR-T

Some doctors reported that a few patients with B-cell cancers treated with FDA-approved DNA-based CAR-T therapy developed lymphoma that contained the CAR-T genetics.

Lymphoma is a cancer of lymphocytes. T-cells are a type of lymphocyte, also called T-lymphocytes. So, if a T-cell becomes cancerous, it is called a T-cell lymphoma. If a CAR-T cell becomes cancerous, it is called a CAR-T lymphoma.

A CAR-T cell lymphoma can occur if a CAR-T cell reproduces uncontrollably and becames cancerous. Fortunately, this rarely occurs. However, each FDA-approved CAR-T therapy had at least one patient develop a CAR-T lymphoma. Therefore, the FDA states it is a “class effect” among CAR-T cell treatments using inserted DNA material.

Since 2017 (the first CAR-T cell product was FDA-approved in 2016), around 30,000 B-cell cancer patients have been treated with DNA CAR-T cell therapies. Therefore, the overall number of CAR-T lymphomas is rare. However, this therapy has been used for only a few years. How many patients could get a CAR-T lymphoma after ten or more years? We do not know.

To put this into perspective, the B-cell cancer patients treated with CAR-T had life-threatening disease, failed multiple standard treatments, and had a high chance of dying without CAR-T treatment. CAR-T cell therapy has induced remission in many patients. Therefore, accepting a rare side effect like this is worth it to most of these patients.

How about CAR-T lymphomas in lupus patients after CAR-T cell therapy?

A big question is for patients with autoimmune diseases, like lupus, most of whom are expected to live long life-spans. Is it worth gambling to possibly develop a CAR-T lymphoma over one’s lifetime, even if the chances are rare?

We do not know if CAR-T lymphoma occurs in autoimmune disease patients treated with CAR-T therapy. So far, no patients with an autoimmune disease have developed CAR-T lymphoma (but the number of treated patients is low). CAR-T cell therapy appears to cause fewer side effects (like complement activation syndrome and severe nerve damage side effects) in lupus patients compared to patients with B-cell cancers. This may have to do with lupus patients having much fewer B-cells killed by CAR-T cell therapy than B-cell cancer patients have.

Lymphoma in DNA vs RNA (and other) CAR-T cell therapies

The CAR-T cell therapies that have caused CAR-T lymphomas have been those where engineered DNA is inserted into the patient’s T-cells (described in detail with the illustrations above). These CAR-T cells multiply (replicate) inside the patient’s body, allowing a rare CAR-T cell to become cancerous, multiply without stopping, and become a cancerous CAR-T lymphoma. CAR-T cell therapies that do not use DNA (like Chimeric autoantigen T-cell receptor (CATCR) T-cell therapies, CAART therapies and RNA CAR-T therapies like Descartes-08) do not reproduce inside the patient’s body and, therefore, should not become cancerous. Autoimmune disease patients may want to consider these forms of CAR-T rather than the DNA-engineered CAR-T if overly concerned about CAR-T lymphoma.

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CAR-T cell therapy side effects seen so far in lupus patients

So far, at least 43 SLE patients have been treated with CAR-T therapy (described below). ICANS was not seen in any of them (as of November 2023 reports). Two of three patients with antisynthetase syndrome (described below) developed mild ICANS that resolved on its own.

CAR-T cell treatments for B-cell cancers also often result in a complete loss of B-cells for a long time. This could increase the risk of some side effects, like infections. CAR-T cell-treated SLE patients also develop a complete loss of circulating B-cells. However, B-cells begin to come back after around 100 days. Most importantly, these appear to be normal B-cells, not the bad ones that previously produced the dangerous lupus autoantibodies (like anti-dsDNA). This is important because normal B-cells are essential for fighting off infections and responding correctly to vaccinations.

CAR-T cell therapy for lupus can cause many other potential side effects. One of the most important, especially in the case of autoimmune disease patients, is that of infections due to chemotherapy and low B-cell levels. Patients treated with two chemotherapy drugs (cyclophosphamide and fludarabine) end up with very low white blood cell counts (white blood cells are necessary for fighting off infections). The CAR-T cells cause a total absence of B-cells for approximately three months in SLE patients. Fortunately, no CAR-T cell-treated SLE patients (43 thus far) have had severe infections.

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CAR-T cell-treated systemic lupus erythematosus patients (as of April 2024)

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The first lupus patients described in the medical literature

In 2021, doctors at the University of Erlangen-Nuremberg (led by Dr. Georg Schett) treated a 20-year-old woman with severe systemic lupus erythematosus (SLE) with CAR-T cell therapy. She had kidney, lung, heart, joint, and skin involvement, along with high anti-dsDNA and low C3 and C4 complement levels. She had failed numerous therapies, including hydroxychloroquine, steroids, cyclophosphamide, mycophenolate mofetil (CellCept), tacrolimus, belimumab (Benlysta), and rituximab (Rituxan). The treatment was safe and caused no significant side effects. She went into complete remission, including normalization of her anti-dsDNA and complement levels, by day 44 after CD-19 CAR-T cell infusion. As of June 2024, she was still in remission, more than 2 1/2 years after one CAR-T cell treatment, living an excellent quality of life and taking no lupus medications.

Note: although she is the first lupus patient reported in the medical literature, Chinese doctors treated 2 lupus patients with CAR-T therapy around 1 1/2 years previously. However, their doctors published their results later (described below).

This report on the 20-year-old woman was followed by 4 additional patients in 2022 with severe, treatment-resistant SLE who had similar results as the first patient (remission, improved energy, and few side effects). Anti-Smith antibody even resolved, which we do not typically see happen in well-treated SLE patients, even those who go into remission with treatment. Three patients had high levels of interferon-alpha before therapy and, after therapy, had no detectable levels. Interferon-alpha is a cytokine (immune system molecule communicating between cells) that is elevated in most patients with moderate to severe systemic lupus. The resolution of interferon-alpha is remarkable. (As a side note, the FDA-approved lupus drug Saphnelo works by interfering with interferon type 1 and interferon-alpha activity).

In February 2024, Dr. Schett’s team reported the results of all 8 initially treated patients (including an additional 3 patients). It showed that all 8 SLE patients went into and stayed in remission (with no significant side effects). All of them have more than a year since their CAR-T cell therapy. Five patients developed CRS, and three patients needed one dose of tocilizumab (Actemra) for cytokine release syndrome and did well. One patient developed pneumonia, and 3 patients developed new-onset hypogammaglobulinemia (low globulin levels that increase the risk of infection). One patient had pre-existing hypogammaglobulinemia due to previous rituximab therapy. Upper respiratory tract infections (URTI) were common, and 4 patients developed COVID infection. However, COVID and URTIs are common in the general population as well.

No patients developed ICANS.

The first lupus patients treated with CAR-T therapy were in China

In China, 13 patients with severe SLE were treated with BCMA combined with CD-19-directed compound CAR-T cells (discussed below) and were reported in November 2023. Although Dr. Georg Schett’s patients described above were described in the medical literature first, the first patients treated in this Chinese series received CAR-T cell therapy earlier. All thirteen patients went into drug-free remission, and there were no major side effects. All dangerous lupus autoantibodies disappeared. Normal B-cells producing important immune system molecules (immunoglobulins) returned in all patients. All patients have been followed for over a year, and two patients for over 3 ½ years. These two patients were the first in the world treated with CAR-T cell therapy (per published reports to date).

Another 12 Chinese patients treated with BCMA/CD-19 CAR-T

Another Chinese site, Zhejiang University School of Medicine, Hangzhou, China, reported treating 12 patients with severe, treatment-resistant SLE with CAR-T cell therapy directed towards both BCMA and CD-19. This group used both low-dose and higher-dose CAR-T. All patients developed mild, treatable CRS, and none developed ICANS. Several developed infections (2 neocoronavirus, one pneumonia, and one gastrointestinal tract) that resolved with treatment. All patients achieved low-disease activity or remission. The doctors reported these results in a brief report (called an abstract). They did not give all the details, such as which patients went into remission and which did not. However, it is remarkable that all these patients with severe SLE went into at least low disease activity.

Novartis’ YTB323 CAR-T therapy (rapcabtagene autoleucel) and SLE

6 SLE patients were treated with a CAR-T cell therapy called YTB323 (rapcabtagene autoleucel) (discussed below) and reported on in March 2024. Cytokine release syndrome occurred in 4 patients and was treatable and resolved in all four patients.  Only 4 of the patients were assessed long enough after CAR-T infusion to assess disease activity. All 4 improved (by the SLEDAI score and physician global assessment), and one patient went into drug-free remission. Five of six patients’ anti-dsDNA levels decreased.

None of their patients developed ICANS. Low gammaglobulin levels were a common side effect. This finding increases the potential for infections. Novartis reported that one patient developed pneumonia but did not require intensive care unit care.

This appears to be a promising CAR-T cell therapy, and I look forward to their future data results.

Kyverna’s KYU-101 used in lupus nephritis

In March 2024, Kyverna reported early results using their KYU-101 CAR-T therapy in two SLE patients with lupus nephritis. They reported results at 28 days after CAR-T infusion for one patient and 90 days for the second patient. Unfortunately, they did not report how their lupus nephritis was doing (i.e., whether proteinuria improved or not). However, anti-dsDNA, C-reactive protein, and complement levels improved in both. One patient had a low platelet count due to SLE (thrombocytopenia) and it resolved after CAR-T therapy.

Pediatric SLE patients treated with CAR-T

A Rome, Italy group treated a 15-year-old SLE patient with severe, treatment-resistant lupus nephritis with CD-19-directed CAR-T cell therapy that was produced using the 2nd generation Prodigy device. Her disease severity went from a SLEDAI score of 12 (severe disease activity) down to 2 (low disease activity). I assume her lupus nephritis may have gone into remission since all the renal domains of the SLEDAI have a score of 4 and higher. Her ANA and anti-dsDNA levels decreased. She did develop grade 2 CRS with fever, rash, and fluid around the lungs (pleural effusion), but these were treatable.

Dr. Georg Schett gave a CAR-T cell therapy lecture at the 2024 European Lupus Society (SLEuro) meeting in Bruges, Belgium, in March 2024. He described a 15-year-old girl with severe lupus nephritis who was treated with a CD-19 CAR-T cell therapy. He showed one slide on the case and stated that the report was “in print” and not formally published yet. She started with very high disease activity (SLEDAI score of 22; anything above 10 is a high disease), and she went into remission after treatment. When treated, she was in complete kidney failure with an estimated glomerular filtration rate (eGFR, a measure of kidney function) of 8 mL/min/1.73m2 (below 10 usually requires dialysis). After treatment, her eGFR improved to 42 mL/min/1.73m2. Her proteinuria decreased from a whopping value of 8660 mg/24 hours of protein down to around 2000. These are truly remarkable results.

At least 43 severe SLE patients treated with CAR-T therapy as of March 2024

So far, at least 43 SLE patients have been treated with CAR-T cell therapy (all described above). Most have gone into drug-free remission. Treatment was overall safe. Most patients developed treatable CRS. No SLE patients have developed ICANs in these reports.

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Other autoimmune diseases treated with CAR-T 

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Systemic sclerosis (scleroderma) patients treated with CAR-T therapy

This same group of German doctors used the same CD-19 CAR-T cell therapy in 3 patients with severe systemic sclerosis (scleroderma) and reported their findings in November 2023. All three had profound improvements in some areas (such as the resolution of finger ulcers and improvements in hand function and lung inflammation) and stabilization in other permanently damaged organs. No severe side effects were seen. These were 6-month results.

Myositis patients treated with CAR-T therapy

The same German group also reported the results of CAR-T cell therapy in 3 patients with a severe form of inflammatory myositis called anti-synthetase syndrome (ASS). ASS is usually severe, causing inflammation of the lungs and muscles, and is often accompanied by other problems, like arthritis and rash. It isn’t easy to treat. Two patients were in remission six months and one year after treatment, respectively. The third patient was still awaiting final assessment. All three patients developed cytokine release syndrome (discussed above). Their CRS was successfully treated with tocilizumab in all three. Two patients developed coordination problems (ataxia) due to a nerve complication called ICANS (discussed above). This was mild and resolved in both patients. With all three patients developing some significant side effects, very close monitoring should be done in the future in patients with ASS.

Myasthenia gravis patients treated with BCMA CAR-T therapy

14 patients with myasthenia gravis (an autoimmune disease that attacks muscles) were treated with Descartes-08 (A BCMA CAR-T, described below). After nine months, all had significant improvements. None had major side effects. CRS and ICANS did not occur. Six months after CAR-T therapy, myasthenia gravis antibodies increase, possibly becoming clinically important at the one-year mark. Therefore, therapy may need to be repeated regularly (such as yearly).

Neuromyelitis Optica

Neuromyelitis optica (NMO) is a severe autoimmune disease that attacks nerves of the brain and spinal cord and can be deadly. Doctors gave BCMA-directed CAR-T cell therapy to 12 patients with severe NMO and reported their results in March 2024. After therapy, all patients improved, reported less disability, and had better quality of life. Eleven of the 12 patients had not flared, and all patients’ AQP-4 antibodies decreased. This is significant since the AQP-4 antibody is important in causing inflammation and damage in this disease. Reduced levels are usually associated with better disease control. The median duration of follow-up was only 5.5 months. Therefore, we look forward to longer follow-up reports on these patients in the future.

Some patients with NMO have other autoimmune diseases (like SLE, Sjogren’s, and rheumatoid arthritis). Three of these patients also had Sjogren’s disease, and one had rheumatoid arthritis, and their results are noted below.

Sjogren’s Disease

Sjogren’s disease is an autoimmune disease that attacks the fluid-secreting glands of the body. Dry mouth, dry eyes, dry itchy skin are some of the problems it causes but it also frequently attacks other organs like the nerves, lungs, liver, and kidneys. Three of the NMO patients described above, treated with BCMA CAR-T cells, also had Sjogren’s disease. We do not have final results on one of the patients. However, two patients had impressive results with improvements in dry eyes (improved tear break up time and Schirmer’s tests), dry mouth (improved unstimulated salivary rate testing), and reduced disease activity as measured by ESSDAI. One patient’s anti-SSA was completely resolved while the other’s anti-SSA markedly decreased. It will be interesting to see if it resolves as well over time.

These results suggest that anti-SSA may be produced primarily by the plasma cells of the body rather than by younger B-cells. BCMA may be a better CAR-T target than CD-19 for anti-SSA-positive Sjogren’s disease, if this is true.

Rheumatoid Arthritis

One of the NMO patients reported above, treated with BCMA CAR-T, also had rheumatoid arthritis, an autoimmune disease that causes deformed, crippled joints if not treated. The BCMA-directed CAR-T therapy resulted in remission for the patient.

NOTE: I did not do an exhaustive search for all autoimmune diseases that may have been treated to date with CAR-T therapy. Above are the ones I found. If you know of others, please comment above at “Leave a Comment.)

Could CAR-T Cell therapies be a cure for autoimmune diseases?

So far, there are no cures for autoimmune diseases like SLE. We can treat them, but most patients must take medicines for the rest of their lives (especially SLE patients).

If any of the patients above who are in drug-free remission stay that way for the rest of their lives, then “YES!” those patients can be said to have been cured of their disease by CAR-T cell therapy. Wouldn’t that be wonderful? We must wait and see.

One thing to note is that three SLE patients treated with CD-19 CAR-T reported above were anti-SSA positive. Although the anti-SSA levels decreased, it did not disappear. This tells me that at least in some patients, autoreactive B-cells producing “bad” autoantibodies can persist after CD-19 CAR-T cell therapy for lupus. One must wonder if there could be a chance for recurrence of SLE in that patient in the future.

Interestingly, the BCMA therapy used in the two Sjogren’s patients caused one patient’s anti-SSA to resolve and the other’s to become normal. It was still decreasing when checked last time, so it may also resolve (but we do not know). Since BCMA-directed therapy targets plasma cells rather than younger B-cells, these results suggest that the plasma cells may be most important in producing anti-SSA. BCMA-directed therapies may be best for Sjogren’s disease, but this is only conjecture on my part.

This raises the question of whether some SLE patients are more likely to respond to some CAR-T cell treatments than others. It will become essential to see if this can be figured out beforehand using newer technology, such as machine learning-assisted endotype identification.

CAR-T cell therapy will not improve symptoms due to permanent damage

Many patients with autoimmune diseases like lupus often have permanent organ damage. Around one in three SLE patients will have organ damage a year after their diagnosis, and around half will have organ damage after five years. Some areas of organ damage will result in problems that cannot be reversed by CAR-T therapy. This includes pain from joint, tendon, and muscle damage; vision loss from eye damage; shortness of breath or chest pain if lung or heart damage; and permanent hair loss or skin color changes from skin involvement like discoid lupus. SLE patients and others must realize this before starting CAR-T cell therapy for lupus.

CD-19 CAR-T Cell treated patients still respond to vaccines

A big problem with some B-cell-depleting therapies, such as rituximab, is that they cause a loss of response to vaccines. Some of the sickest COVID-19 patients I saw (including deaths) during the COVID-19 pandemic were rituximab-treated patients who did not respond to the COVID-19 vaccines.

The 8 CAR-T treated SLE patients reported on in 2022-2023 by Dr. George Schett’s group showed that they still had vaccine responses to previous rubella, measles, mumps, Epstein Barr virus, varicella zoster, pneumococcus, and tetanus vaccines. This is important because it means patients do not need to be revaccinated.

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Advice for lupus patients after CAR-T cell therapy

Although the CAR-T cell-treated patients have thus far had impressive disease-free results after treatment, lupus patients still have the genetic predisposition for developing problems from the disease again. Scientists have discovered over 180 genes that increase the risk of developing lupus.

For example, although the CAR-T treatment rids the body of bad B-cells that produce dangerous autoantibodies, we are not sure these “bad” B-cells primarily cause these disease. SLE has other types of overactive white blood cells (such as T-cells, dendritic cells, and polymorphonuclear cells).

Other immune system abnormalities exist in SLE patients, such as complement deficiencies and overproduction of some immune system molecules (like type I interferon). If SLE is primarily caused by one of these non-B-cell mechanisms, then that person is at risk for the disease returning. Also, SLE patients probably differ in what mainly drives their disease.

How to possibly prevent lupus from returning after CAR-T therapy

I have some recommendations for SLE patients treated with CAR-T (but please check with your treating rheumatologist; I cannot give formal medical advice without knowing the reader’s entire history, physical exam, labs, and medical history).

Consider taking hydroxychloroquine after CAR-T Cell therapy for lupus

Hydroxychloroquine (HCQ, Plaquenil) is one of the safest drugs to treat SLE. HCQ has numerous benefits in SLE patients, such as reducing the risk of major organ involvement and antiphospholipid antibody production. More importantly, it may reduce the evolution of “at-risk” people in developing SLE, which is pertinent to its use after CAR-T therapy.

In addition, the most significant potential side effect of HCQ, vision loss due to eye damage from retinopathy, should be rare as long as patients get a yearly visual field 10-2 and a yearly spectral domain ocular tomography coherence test. People of Asian descent should get an annual third test (a VF 24-2 or a VF 30-2).

Therefore, I would recommend that patients consider taking hydroxychloroquine and avoid the following lupus triggers after CAR-T therapy.

Avoid situations that can trigger the occurrence of lupus

Most people born with the genes that cause SLE do not develop SLE. Environmental triggers probably play a prominent role in people developing SLE. Therefore, it makes sense to avoid known lupus triggers as much as possible (see the list below):

• Abide by ultraviolet light–protection measures (click the UV light icon at the bottom of the Lupus Secrets page).
• Floss and brush teeth daily to help prevent periodontal disease and tooth decay.
• Ask your doctor to monitor your vitamin D level; take a vitamin D supplement if it is less than 40 ng/mL.
• Never smoke cigarettes; avoid second-hand smoke.
• Avoid sulfa antibiotics (add to allergy list).
• Do not eat alfalfa sprouts or mung bean sprouts.
• Consider healthy use of moderate alcohol drinking when old enough (ask your doctor first).
• Eat a diet rich in omega-3 fatty acids (flaxseed, cold-water fish, chia seed, walnuts, etc.).
• Consider eating “resistant starches” regularly (legumes, peas, overnight oats, etc.).
• Consider decreasing exposure to phthalates (lipstick, plastics, cosmetics).
• Learn to cope with stress; do daily breathing exercises, and practice mindfulness.
• Get at least 7 hours of sleep each night.
• Avoid the herbal supplement Echinacea.
• Avoid exposure to pesticides.
• Avoid using hair dyes.

CAR-T cell therapy may not help some systemic inflammatory diseases

So far, CAR-T cells have been designed to destroy B-cells. Therefore, systemic autoimmune diseases where the B-cells produce dangerous autoantibodies that attack the patient’s tissues are most likely to benefit. Thus far, CAR-T cell therapy has helped patients with some of these diseases, including SLE, systemic sclerosis (also called scleroderma), anti-synthetase syndrome polymyositis, and myasthenia gravis. CAR-T therapy has also helped mice with a multiple sclerosis-like disease.

Hopefully, CAR-T cells will help other autoimmune diseases where B-cells produce autoantibodies. These other diseases that could potentially benefit include rheumatoid arthritis, Sjögren’s disease, antiphospholipid syndrome, Grave’s disease, pemphigus, polyangiitis with granulomatosis, and microscopic polyangiitis (to name a few). Some of these diseases, like Sjögren’s disease and systemic sclerosis, have very few effective therapies today. CAR-T cell therapy could significantly improve their treatment if it proves safe and effective for these diseases.

However, I am concerned with Sjögren’s disease, which can have a high burden (large amounts) of B-cells. This could increase the risk for CRS and ICANS, as discussed above. CAR-T cell therapies showing low CRS and ICANS cases should be considered in Sjögren’s disease clinical trials. Such possible therapies that may not cause more side effects in those with a high B-cell burden include Descartes-08 and CAAR-T Therapy.

Diseases that do not have B-cells producing dangerous autoantibodies are unlikely to be helped with these CAR-T cells. This includes diseases like psoriatic arthritis, Crohn’s disease, ulcerative colitis, and ankylosing spondylitis. However, it is possible to use CAR-T cell technology to target other parts of the immune system. I discuss some possibilities below.

The future of CAR-T Cell therapy for people with autoimmune diseases

SLE patients are now enrolling in CAR-T cell therapy clinical trials (listed at the end of this blog post). CAR-T cell therapy would probably become available for SLE patients with severe, treatment-resistant disease if these prove to reproduce effective, safe results.

But how about patients with milder disease? Around 30% of SLE patients in my clinic go into remission using hydroxychloroquine, UV light protection (like daily use of sunscreen), and vitamin D treatment.

However, the rest require immunosuppressant therapies that carry the potential for more side effects, like infections. This group of patients also has higher medical expenses, especially when you factor in emergency room visits, hospitalizations, twice-yearly eye exams for hydroxychloroquine, and multiple doctor visits. Some patients require very expensive biologic drugs and infusions. All this adds up over the patient’s lifetime. Most SLE patients live long, normal life spans.

Treat mild lupus with CAR-T therapy?

Even though CAR-T cell therapy costs around $400,000 for one patient, this is much less than most SLE patients will need during their lifetime to treat their SLE. A Johns Hopkins (Baltimore, Maryland) study reported 2015 lupus costs of around $20,000 per year for patients with mild disease. Indeed, this would be much higher today in 2023. Even with these figures, one CAR-T cell treatment for a patient with mild SLE would equal the cost of less than 20 years with conventional therapies. The vast majority of 20-year-old patients with mild SLE would be expected to live well past 40 years of age.

The cost of drugs for patients with severe SLE can be as high as $100,000 per year. The cost savings in these patients would be met within just a few years after successful CAR-T cell therapy.

If CAR-T cell therapy were to result in permanent remissions, the overall therapy costs would be well worth it. This is not even considering the hidden costs related to better quality of life, work productivity, time saved by not seeing doctors as often, not missing out on social events due to not feeling well, and the freedom from taking medications all the time.

A big obstacle with using DNA CAR-T cell therapy in people with mild lupus is the possibility of CAR-T lymphoma. Few patients with mild lupus would want to take such a risk. If CAR-T therapies that do not cause CAR-T lymphomas (such as the RNA CAR-T cell treatments like Descartes-08) are proven safe and effective, then they would be a more reasonable option. However, their cost could be prohibitive for mild lupus since these therapies may require repeated infusions and therefore are expensive.

Retreating patients with CAR-T cell therapy

If the autoimmune disease returns after CAR-T therapy, retreatment is possible. There should be frozen (cryopreserved) CAR-T cells saved from the patient’s initial preparation. If the patient had a prolonged remission with few to no major side effects, retreatment with these cryopreserved cells could be considered.

CAR-T cell therapy in doctors’ offices vs hospitals

CAR-T cell therapy is complex. Doctors and nurses must closely monitor treated patients for potentially dangerous side effects (discussed previously). Due to the need for rapid identification and proper treatment of side effects, CAR-T cell therapy for lupus patients is administered in specialized centers where highly-trained specialists are available. This includes rheumatologists, hematologists, nephrologists, pulmonologists, and neurologists.

One CAR-T cell therapy for lupus with the advantage of outpatient treatment (doctor’s offices) that is much more convenient is Descartes-08 by Cartesian. Patients treated with Descartes-08 had no problems with either cytokine release syndrome or neurologic problems like ICANS.

If studies confirm the safety of other CAR-T therapies, it could evolve to being administered in outpatient settings in doctors’ offices by other brands as well.

CAR-T cell therapy research study designs

We always like to have randomized, double-blinded, placebo-controlled trials (RCTs) for drug treatments. This means some patients receive fake treatment (placebo), and neither the doctors nor the patients know which they get (the study drug or the placebo).

A downside to CAR-T therapy research is that some require the destruction of lymphocytes using chemotherapy (cyclophosphamide and fludarabine) before getting CAR-T. You cannot give fake (placebo) treatment to these patients and put them at higher risk for infections. Researchers are currently discussing ways to get around the placebo obstacle so that high-quality studies can be done.

Another improvement that researchers should consider for future CAR-T cell therapy research studies is to improve the identification of cytokine release syndrome (CRS). When patients in a CAR-T cell therapy research study develop fever, this is often attributed to CRS. However, patients in the Descartes-08 CAR-T cell therapy research study who developed fever as a side effect did not have the immunologic features of CRS. Therefore, researchers should define CRS using its known immunologic abnormalities rather than a symptom like fever, which other mechanisms could cause.

CAR-T cells from donors (allogeneic CAR-T cell therapy)

The T-cells used to produce CAR-T cells in this blog post came from the patients (called autologous CAR-T cell therapy). Potential problems with this include the fact that these T-cells may not be healthy. They contain the genes that predispose the person to their autoimmune disease. In addition, they may be damaged by previous treatments with immunosuppressants like mycophenolate, steroids, azathioprine, methotrexate, and cyclophosphamide.

Therefore, research is now looking at possibly producing CAR-T cells from healthy donors (called allogeneic CAR-T cells). Initial studies show that allogeneic CAR-T cells work in treating leukemia patients.

Allogeneic CAR-T cell therapies are recruiting patients for clinical trials. In April 2024 I became aware of Fate Therapeutics’ version of a CD-19 CAR-T called FT819.

Suppose this proves to work for autoimmune disease patients. In that case, some advantages include that the allogeneic CAR-T cells are more likely to have healthier genes and not be exposed to immunosuppressant drugs.

In addition, producing autologous CAR-T cells from the T-cells of a patient (autologous T-cells) is a lengthy, complicated procedure that takes time and could fail at any point in the complex process. CAR-T cells from other individuals (allogeneic) could be stored in a doctor’s office and infused as soon as needed, eliminating long wait times.

Figure out which lupus patients will respond best to different types of CAR-T therapies

One of the studies mentioned below (KYV-101 by Kyverna) will study 24 different immune system cells throughout the study to better understand what happens with the immune system after CAR-T therapy. The FDA awarded fast-track designation to Kyverna’s KYV-101 CAR-T clinical trial.

I hope other companies take similar measures to look deeply at the immune system and patient endotypes to understand better what happens. If some CAR-T therapies work in some SLE patients but not in others, it will be essential to figure out which patients are most likely to respond ahead of time. This sort of research is already being done in some SLE drug trials.

CAR-T cells that target only specific “bad” B-cells (leaving healthy cells alone)

Currently, CAR-T cell therapy attacks and destroys all the B-cells in the treated patient. In SLE patients, the B-cells have recovered after around 100 days. However, they have an extended time before this 100 days when there is an absence of B-cells, placing the patient at risk for infections.

Chimeric autoantigen T-cell receptor (CATCR) T-cell therapy

In November 2023, the Johns Hopkins Division of Rheumatology, Baltimore, Maryland, reported a fascinating study. They developed chimeric T-cells (CATCRs) programmed to destroy B-cells that make a specific autoantibody (an antiphospholipid antibody called beta-2-glycoprotein-1 antibody). This was created using CRISPR technology that edits the genes of T-cells. Instead of destroying all the B-cells in the patient (as what happens with CD-19 CAR-T), this method kills only the B-cells that produce that one antibody. This could be helpful in patients with only one “bad” type of B-cell. In SLE, this may be very difficult since there are usually numerous types of “bad” B-cells making dangerous autoantibodies. Nonetheless, this sounds fascinating and helps paint a brighter future.

Regulatory T-cells (Tregs) engineered with specific T-cell receptors (TCRs)

Abata Therapeutics has designed Tregs with TCRs that recognize the actual damaged tissue (in this case the damaged covering of nerves in myasthenia gravis and the damaged insulin producing cells in diabetes type 1). When the infused Tregs come into contact with the damaged tissues, they release substances (cytokines) that decrease inflammation directly at the area (tissue) involved instead of acting throughout the body. They plan on starting clinical trials for myasthenia gravis in 2024 and for diabetes type I in 2025. Like Descartes-08, chemotherapy will not be used for this treatment.

Chimeric autoantibody receptors (CAARs)

CAARs are T-cells that recognize specific “bad” B-cells (autoreactive B-cells). They are engineered only to identify the autoantibodies on the surface of “bad” B-cells, destroy them, and leave healthy B-cells alone. While CD-19 CAR-T cell therapy is likened to hitting the B-cells with a “sledgehammer,” CAAR T-cells are compared to striking the B-cells “like a razor’s edge.” Cabaletta Bio is testing its CAAR T-cells for the skin autoimmune disease called pemphigus.

CAR-T cells that target cells other than B-cells

Fibroblasts are cells that produce damaging scar tissue in autoimmune diseases like rheumatoid arthritis, Sjögren’s disease, and scleroderma. A team in Oxford, United Kingdom, studied CAR-T cells that targeted “bad” fibroblasts in mice with inflammatory arthritis. It showed positive results. Could targeting fibroblasts be a good option? It does have the potential for fewer infections since it does not involve depleting white blood cells. No human studies have been done yet (as of April 2024).

An American group presented laboratory data on a type of CAR-T cell directed at antigen-presenting cells (APCs). APCs play a central role in the immune system abnormalities in SLE. Some SLE patients specifically have abnormal genetic formation of molecules on APCs that may drive their disease. This could be a viable option for these patients. This is very preliminary, and I suspect animal lupus studies would be the next step.

Other Potential CAR-T targets 

CD-19 is the target antigen of the CAR-T cells used in most autoimmune disease patients up to this date. However, it is not clear if this is the most effective target. CD-19 is located in all stages of B-cells, excluding the most mature type called plasma cells. One potential problem with this is that the plasma cells may be in important producer of some autoantibodies (like anti-SSA) and therefore may not thoroughly “reset” the immune system. However, thus far, this target appears to be doing well up to several years after CD-19 CAR-T cell therapy. We need to see what happens in these patients after 5-10 years.

Some patients may possibly do better with CAR-T cells aimed at another target, listed below.

CD-20 and CD-22 CAR-T cells

CD-20 and CD-22 are on all the cells CD-19 is, except they are not on immature plasma cells, called plasmablasts, and on plasma cells (mature plasmablasts). It is unknown if CD-20 or CD-21 would make better CAR-T cell targets. However, CD+ T-cells do appear to play an inflammatory role in autoimmune diseases, and CD-20 targeted CAR-T therapy may potentially play a role in its effects on these T-cells as well as the B-cells. There is one CAR-T cell product called IMPT-514 that targets CD-20 and CD-21. It is described below.

BCMA and CD-38 CAR-T cells

CD-38 and a B-cell membrane antigen called B-cell maturation antigen (BCMA) are also attractive targets. They work very differently than CD-19 since they are located on the most mature B-cells (memory B-cells), plasmablasts, and plasma cells.

If some SLE patients have more plasma cell-driven disease (such as via anti-SSA antibodies), these may be good alternative targets. A potential downside of this therapy is that plasma cells are essential for ongoing antibody production, which it learned to do before CAR-T therapy. Due to this loss of plasma cells, it is possible that patients treated with CD-38 or BCMA CAR-T cells may lose their previous vaccine responses and have to be revaccinated. This is theoretical and needs to be studied.

Cartesian Therapeutics’ Descartes-08: a novel mRNA BCMA CAR-T therapy

Cartesian Therapeutics in Gaithersburg, Maryland, produces a BCMA CAR-T cell therapy called Descartes-08. They plan on starting a clinical trial using Descartes-08 in SLE patients soon. Descartes-08 has already been used successfully in 14 myasthenia gravis patients (discussed previously).

Cartesian plans on not giving chemotherapy before treatment in its SLE clinical trials. A potential advantage of not giving chemotherapy is the possibility of fewer infections. Patients with severe SLE will receive six weekly infusions.

Another potential advantage of Descartes-08 is that it uses mRNA technology instead of DNA. Most CAR-T cell therapies have virus-inserted DNA that produces the antigen receptor. The problem with using DNA is that it causes a large reproduction of many additional CAR-T cells inside the patient. Reproducing numerous CAR-T cells inside the patient leads to activating immune system molecules called cytokines. This is probably a significant reason for the many cases of CRS and ICANS discussed above.

Because of the lack of the above severe side effects, Descartes-08 can be given to patients in their doctor’s office, making it much more convenient than going to a hospital as with other brands (as of January 2024).

Inserting RNA (also called transfecting RNA) into patients’ T-cells to make CAR-T cells (instead of using lentivirus to insert DNA) is theorized to be safer. Since the CAR-T cells are reproduced in large numbers in the lab instead of in the patient, the immune system activation and extensive cytokine production should not occur as with DNA technology. The Descartes-08 studies in myasthenia gravis had no CRS or ICANS cases.

Over time, the amount of RNA CAR T-cells decreases and eventually disappears. Since they target cells that contain BCMA (plasma cells and plasmablasts), premature and mature B-cells produce more plasmablasts and plasma cells, increasing the risk for the re-emergence of autoantibodies. The Descartes-08 studies show that myasthenia gravis antibodies increase around nine months after Descartes-08 CAR-T cell treatment. The levels of autoantibodies stay below the amount considered significant (and cause increased disease activity) until around the one-year mark.

The advantages of Descartes-08 include not needing chemotherapy, outpatient treatments instead of being hospitalized, not causing CAR-T lymphoma, and the total absence of cytokine reactivation syndrome and ICANS (severe nerve damage). This needs to be balanced by the downside of possibly needing ongoing yearly infusions. However, we must wait to see what happens to SLE autoantibodies after Descartes-08 treatment. They may act very differently than myasthenia gravias autoantibodies, which begin to increase around nine months after Descartes-08 CAR-T cell therapy.

Newer CAR-T cell production technologies

DNA-based CAR-T cells must be reproduced in large numbers before infusion into the patient, which takes a long time. New technology can replicate the CAR-T cells in less than 2 days and be used in a much lower dose (25 times less) than other DNA-based CAR-T cells. A CAR-T cell therapy called YTB323 (by Novartis) uses this technology. They are recruiting patients in Australia, Germany, Spain, Switzerland, and France for this study.

Another CAR-T production method called the “NEX-T Process” also uses a shorter production time and allows lower doses of CAR-T. NEX-T Process-produced CAR-T cells may be more effective and have fewer side effects. A clinical trial using CD-19-directed NEX-T CAR-T cells (called CC97540 by Bristol-Myers Squibb and Juno Therapeutics) is recruiting SLE patients at many sites in the United States and Europe. Some are currently recruiting patients. Click on the link to see the contact information.

Current CAR-T Cell Therapy for Lupus Clinical Trials

A search for clinical trials at clinicaltrials.gov (January 2024) shows numerous proposed clinical trials for CAR-T therapy in SLE.

If you are interested in participating in these trials, read over the inclusion and exclusion criteria at the links below. If you do not satisfy these criteria, there are ways of receiving these drugs through compassionate use. Your doctor can contact them at the links if your doctor thinks you would be a good CAR-T cell therapy patient. For any studies that do not list a contact (like the Descartes-08 study), keep checking the link to the study for updates.

There are also clinical trials for other autoimmune diseases like Sjogren’s disease, myositis, scleroderma, myasthenia gravis, and muscular dystrophy listed below. 

SLE CAR-T Cell clinical trials for lupus listed as of December 2023:

Actively recruiting lupus patients for CAR-T cell therapy clinical trials

• An “off-the shelf” allogeneic CD-19 CAR-T product by Fate Therapeutics (called FT819) is recruiting patients at a Nebraska and Minnesota site. Here is more information on FT819, click here.
• YTB323, discussed above, is recruiting SLE patients (including lupus nephritis patients) in Germany, Spain, Switzerland, France, and Australia. If interested in the study, contact Novartis Pharmaceuticals at email@novartis.com, 888-669-6682, or 416-132-1111.
• A CD-19-directed CAR-T cell called CABA-201 (by Cabaletta Bio) was recruiting SLE patients in Boston, Massachusetts. A site at UC Davis Health in Sacramento, California, will be recruiting patients soon. You can contact Cabaletta Bio at 267-759-3100. This study lists Tammy Trotter at tkyotter@ucdavis.edu and 916-734-6944 as the primary contact. The FDA awarded two different fast-track designations for Cabaletta Bio’s CABA-201: one for SLE and one for dermatomyositis.
• Bristol-Myers-Squibb is recruiting SLE patients in the United States and Europe (numerous sites) for its CD-19-directed NEX-T CAR-T cell therapy called CC97540 (discussed above).
• Kyverna Therapeutics is recruiting patients with refractory lupus nephritis for its CD-19-driven CAR-T therapy for lupus called KYV-101. Their research sites are in Denver, Colorado, and Great Neck, New York. Contact Kyverna at ClinicalTrials@kyvernatx.com and 510-925-2484 if interested. Kyverna will use an artificial intelligence platform called the Immune Profiler by Verily in its study. This will track 24 different immune cell types throughout the study, allowing a much deeper dive into the effects of CAR-T therapy.
• Miltenyi Biomedicine is recruiting SLE patients for its CD-19 CAR-T called MB-CART 19.1. The first five patients with severe SLE and lupus nephritis were treated with MB-CART 19.1 in Germany, reported in November 2023; all went into remission with few significant side effects.
• CD-19 CAR-T therapy for lupus nephritis patients who have failed other therapies at Great Neck, New York, and Denver, Colorado

CAR-T cell therapy for lupus clinical trials that will soon be recruiting patients

• CAR-T therapy targeting CD-19 and CD-20 (IMPT-514) at the University of California Los Angeles is actively recruiting patients in San Francisco and Los Angeles. To inquire about the study, click on this clinical trials .gov link.
• Descartes-8 (an mRNA-based CAR-T cell therapy discussed above) is a proposed clinical trial in SLE Cartesian Therapeutics is recruiting patients at a San Diego Site.
• Pharmaceutical company Galapagos (which has both US and European offices) is planning an SLE clinical trial for its CD-19 CAR-T called GLPG5101. Its leukemia studies showed no severe CRS or ICANS cases.
• Autolus Therapeutics plans a clinical trial in SLE for its CD-19 CAR-T called Obe-cel in 2024.
• Sana Biotechnology has applied to the FDA to do a clinical trial in SLE and ANCA-associated vasculitis patients using SC291, allogeneic (meaning they come from donors and not from the patients themselves) CD-19 CAR-T cells.
• iCell Gene Therapeutics is planning a clinical trial in the US using a compound CAR-T (cCAR-T) directed towards CD-19 and BCMA in patients with severe SLE.
• Dr. Georg Schett and his team (the same team that reported on the first published treated SLE patients) will be using MD CAR-T 19.1 in severe SLE patients in Germany.

Chinese CAR-T cell therapy for lupus clinical trials

• Chinese sites were recruiting patients for CD-19-targeted CAR-T cell therapies.
• Numerous others for CD-19 were not recruiting yet. One study in China was recruiting subjects with SLE, Sjogren’s disease, systemic sclerosis, inflammatory myositis, ANCA-positive vasculitis, and antiphospholipid syndrome using allogeneic CAR-T cells (from donors instead of from the patients themselves. The name of this CAR-T cell therapy is Universal CAR-T cells or BRL-301 (Allogeneic Chimeric Antigen Receptor T Cell Injection Targeting CD19 Gene).
• A study in China using CAR-T cells directed at both CD-19 and BCMA was recruiting SLE patients.
• Another Chinese study using BCMA-targeted CAR-T cells was recruiting SLE patients.

CAR-T cell therapy clinical trials for other autoimmune diseases

• Myasthenia gravis patients with Descartes-08 in multiple US sites = they are recruiting patients
• MuSK-positive myasthenia gravis, multiple US sites
• Inflammatory myositis, University of California Irvine (Cabaletta Bio’s CABA-201 for dermatomyositis, polymyositis, anti-synthetase syndrome, and immune-mediated necrotizing myopathy)
• Multiple sclerosis, Palo Alto, California using CD-19 CAR-T cells; and another study by Abata Therapeutics using engineered Tregs with specific TCRs (to begin in 2024)
• Diabetes type I by Abata Therapeutics using engineered Tregs with specific TCRs (to begin in 2025)
• Pemphigus using CAAR T-cells (DSG3-CAART) by Cabaletta Bio
• Chinese sites for Sjogren’s disease
• Chinese sites for many different autoimmune diseases

FINAL THOUGHTS ABOUT CAR-T CELL THERAPY FOR LUPUS

Like many others, I am incredibly impressed with the results so far. Critics will point out the low number of patients. We have seen many promising treatments in the past for autoimmune diseases like SLE, where the initial studies looked amazing in small numbers of patients, only to fail when studied formally in large numbers.

However, most patients with severe, treatment-resistant SLE went into complete drug-free remission, not needing any lupus medications for as long as 3 ½ years … that is truly miraculous. No therapy has ever shown such excellent results.

We are entering one of the most exciting chapters in treating these diseases. Wouldn’t it be wonderful if they were proven to be this effective and very safe? I imagine a day when I would diagnose someone with SLE and be able to tell them,

“I have a one-shot treatment that can probably get you into remission and has a low risk of major side effects, and could possibly cure you of your SLE.”

However, my dream is premature. What happens after 3 1/2  years in these patients? I will watch the CAR-T story closely and hope it pans out. Stay tuned to “The Lupus Encyclopedia!”

For more in-depth information on research studies in lupus:

Read chapter 37 of The Lupus Encyclopedia, edition 2

Also, look up your symptoms, conditions, and medications in the Index of The Lupus Encyclopedia

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What are your comments and opinions?

If you have lupus, what has your experience been? What do you recommend for other patients?

If you know of any CAR-T cell therapies I missed above, please let me know in the Comments.

Do you have any questions to ask Dr. Thomas?

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