CD19 CAR T-Cell Therapy for Autoimmune Diseases: A 15-Patient Case Series

Table of Contents

• Key Points
• Background: Why This Research Matters
• What Is CAR T-Cell Therapy?
• How the Study Was Conducted
• Who Were the Patients?
• How the CAR T-Cells Were Made
• CAR T-Cell Expansion and B-Cell Depletion
• Key Findings: Treatment Effectiveness
• Results in Systemic Lupus Erythematosus
• Results in Idiopathic Inflammatory Myositis
• Results in Systemic Sclerosis
• Autoantibody and Vaccine Responses
• B-Cell Recovery After Treatment
• Safety and Side Effects
• What This Means for Patients
• Limitations of the Study
• Recommendations and Next Steps
• Frequently Asked Questions
• Source Information

Key Points

• In a 15-patient case series, a single infusion of CD19 CAR T-cell therapy allowed all patients to stop immunosuppressive medications, with remission in the patients with SLE, a major clinical response in the patients with myositis, and reduced disease activity in the patients with systemic sclerosis.
• All 8 patients with SLE achieved remission, all 3 with myositis had a major response, and all 4 with systemic sclerosis had reduced disease activity.
• Side effects were mostly mild: grade 1 cytokine release syndrome in 10 patients, one grade 2, and one grade 1 neurotoxicity; no severe cases occurred.
• The immune system's ability to fight infections was largely preserved, and patients could still respond to new vaccinations after treatment.
• This was a small, uncontrolled case series; larger controlled trials with longer follow-up are needed to confirm effectiveness and safety.

Background: Why This Research Matters

Autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis are chronic conditions. In these diseases, the immune system mistakenly attacks the body's own tissues. This leads to ongoing inflammation, organ damage, and increased risk of death.

Current treatments for these diseases rely on long-term immune suppression. These drugs can control symptoms, but they rarely cure the disease. Patients often must take them for years or even for life. Achieving lasting remission without drugs has remained an elusive goal.

B cells are a type of immune cell that normally produce antibodies to fight infections. In autoimmune diseases, however, autoreactive B cells (B cells that attack the body's own tissues) drive the disease process. Previous treatments targeting B cells used antibodies. These antibodies either depleted B cells by binding to a surface molecule called CD20, or they blocked B-cell activation by targeting a protein called B-cell activating factor.

Antibody-based B-cell targeting improved treatment for some patients. However, it did not achieve long-lasting, drug-free remission. This is where CAR T-cell therapy comes in. CAR T cells can potentially achieve deep depletion of B cells by targeting CD19, a molecule found on a wide range of B cells and plasmablasts (a type of antibody-producing cell).

Over the past two years, several individual case reports and one small case series suggested that CD19 CAR T-cell therapy might be feasible and effective in autoimmune disease. This new study presents data on both short-term and long-term effectiveness and safety in 15 patients with severe forms of three different autoimmune diseases.

What Is CAR T-Cell Therapy?

Chimeric antigen receptor (CAR) T-cell therapy is a treatment in which a patient's own T cells (a type of immune cell) are genetically modified. The modification gives the T cells a new receptor called a chimeric antigen receptor. This receptor allows the T cells to recognize and attack specific target cells.

CAR T-cell therapy has become a powerful tool for treating cancer, particularly blood cancers. Targeting malignant B cells with CAR T cells has greatly improved treatment for certain lymphomas and leukemias. The same approach can be applied to autoimmune diseases, because autoreactive B cells cause damage in these conditions.

The treatment works by deeply depleting B cells. The CAR T cells target CD19, a surface molecule expressed on a broad spectrum of B cells and plasmablasts. By eliminating these cells, the treatment aims to "reset" the immune system and stop the autoimmune attack.

How the Study Was Conducted

This study was a case series conducted at multiple centers in Germany. The researchers evaluated 15 patients with severe autoimmune diseases. The patients received a single infusion of CD19 CAR T cells.

Before receiving the CAR T cells, each patient underwent preconditioning chemotherapy. This preconditioning used two drugs: fludarabine and cyclophosphamide. The purpose of this chemotherapy is to make space in the immune system for the new CAR T cells to grow and function.

The researchers assessed how well the treatment worked for up to 2 years after the infusion. They used several standardized measurement tools:

• For SLE: The Definition of Remission in SLE (DORIS) remission criteria, the Lupus Low Disease Activity State (LLDAS) criteria, and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). The SLEDAI-2K score ranges from 0 to 105, with higher scores indicating greater disease activity.
• For idiopathic inflammatory myositis: The American College of Rheumatology–European League against Rheumatism (ACR–EULAR) Total Improvement Score. This score ranges from 0 to 100. A score of 0 to 19 means no clinical response, 20 to 39 means a minimal response, 40 to 59 means a moderate response, and 60 to 100 means a major clinical response.
• For systemic sclerosis: The European Scleroderma Trials and Research Group (EUSTAR) activity index. This score ranges from 0 to 10, with higher scores indicating greater disease activity. The modified Rodnan skin score was also used. This score ranges from 0 to 51, with higher scores indicating worse skin fibrosis (scarring and thickening of the skin).

Safety was carefully monitored. Patients were screened daily for cytokine release syndrome (a potentially serious immune reaction). Patients were also screened daily for immune effector cell–associated neurotoxicity syndrome (ICANS, which involves neurological symptoms). Screening occurred during the first 10 days after the CAR T-cell infusion. These conditions were assessed using the American Society for Transplantation and Cellular Therapy consensus criteria.

Myelotoxicity (damage to bone marrow) was defined as grade III or IV neutropenia (low levels of a type of white blood cell). Myelotoxicity was also defined as leukocytopenia (low white blood cell count). The neutropenia or leukocytopenia had to last more than 28 days after therapy. The researchers also monitored CAR T-cell levels, leukocyte subsets, autoantibodies, vaccination-related antibodies, and B-cell populations.

The study was offered through an expanded-access program for critically ill patients in Germany. All patients provided written informed consent. The study followed CARE guidelines for case reports and the principles of the Declaration of Helsinki.

Who Were the Patients?

From February 2021 through May 2023, a total of 15 patients were treated. The group included 8 patients with SLE, 3 with idiopathic inflammatory myositis, and 4 with systemic sclerosis.

All patients had severe, progressive disease. They had all failed to respond adequately to at least two different standard immunosuppressive treatments. The median number of previous treatments was 5, with a range of 2 to 14.

The patients with SLE had active disease. Their median SLEDAI-2K score was 13 (interquartile range, 9.3 to 16). Interquartile range means the middle 50% of values fell between these two numbers. Each SLE patient had at least one severe (A) score on the British Isles Lupus Assessment Group (BILAG) 2004 index. All had histologically proven glomerulonephritis (kidney inflammation) of World Health Organization grade III or IV.

All patients with idiopathic inflammatory myositis and systemic sclerosis had interstitial lung disease (scarring of lung tissue). Their lung function was reduced. The median forced vital capacity (a measure of how much air the lungs can hold) was 53% in the myositis group (interquartile range, 49 to 64). The median forced vital capacity was 36% in the sclerosis group (interquartile range, 24 to 53). The median diffusing capacity of the lungs for carbon monoxide was 67% in the myositis group. This measure shows how well oxygen moves from the lungs into the blood, and the interquartile range was 49 to 75. The median diffusing capacity of the lungs for carbon monoxide was 59% in the sclerosis group (interquartile range, 34 to 72).

Patients with idiopathic inflammatory myositis showed active muscle involvement. Their median creatine kinase level (a marker of muscle damage) was 4298 U per liter (interquartile range, 766 to 9305). Patients with systemic sclerosis had active skin involvement. Their median modified Rodnan skin score was 25.5 (interquartile range, 18.8 to 30.8).

Eight patients had previously received B-cell–depleting agents. Nine patients had previously received cyclophosphamide, with a median dose of 3 g (interquartile range, 1 to 6; mean ±SD, 5.3±6.9 g).

Some patients had been previously reported in earlier publications. These included Patients 1 through 5 with SLE, Patients 1 and 2 with idiopathic inflammatory myositis, and Patient 1 with systemic sclerosis.

How the CAR T-Cells Were Made

The investigational medicinal product used in this study was called MB-CART19.1. It consisted of the patient's own CD19 CAR–transduced CD4- and CD8-enriched T cells. These cells were derived from a leukapheresis product (a sample of blood cells collected from the patient). The cells were processed using a device called the CliniMACS Prodigy (made by Miltenyi Biotec).

The manufacturing process was highly consistent among the 15 patients. Cell proliferation during manufacturing, transduction efficacy (how efficiently the CAR gene was inserted into the T cells), and the cellular composition of each product were all similar across patients.

In all 15 patients, more than 1×10⁹ (1 billion) CD19 CAR T cells could be produced. Transduction efficiencies ranged from 18% to 44%. Most CD19 CAR T-cell products contained a higher number of CD4+ cells than CD8+ T cells. The exceptions were the product for Patient 8 with SLE and the products for Patients 1 and 4 with systemic sclerosis.

CAR T-Cell Expansion and B-Cell Depletion

After infusion, the CAR T cells rapidly multiplied in the body. They reached peak concentrations after a mean of 8.6±0.8 days (median, 9 days; interquartile range, 9 to 9). At the peak of expansion, the median number of circulating CAR T cells was 146 per microliter (interquartile range, 61 to 697).

CD19+ B cells were rapidly eliminated from the peripheral blood. This happened after a mean of 5.9±2.2 days (median, 7 days; interquartile range, 3 to 7).

In 14 of the 15 patients, B cells reappeared after a mean of 112±47 days (median, 100 days; interquartile range, 72 to 153). The last patient (Patient 4 with systemic sclerosis, with 128 days of follow-up) was still waiting for B-cell recovery at the time of the analysis.

The researchers found that patients previously exposed to B-cell–depleting antibodies had lower B-cell counts at baseline. These patients also had a longer period of B-cell aplasia (absence of B cells). The median B-cell aplasia time was 138 days (interquartile range, 66 to 189) in patients previously exposed to B-cell–depleting antibodies. This compared with 86 days (interquartile range, 70 to 124) in patients who had not been exposed to these antibodies.

In addition, the peak of CAR T-cell expansion was lower in patients who had previously received rituximab (a B-cell–depleting drug) than in those who had not. The median peak was 91 cells per microliter (interquartile range, 38 to 270) in the rituximab-treated group. This compared with 461 cells per microliter (interquartile range, 61 to 1275) in the group that had not received rituximab.

The duration of CAR T-cell presence in the blood was also shorter in patients who had previously received rituximab. The median duration was 40 days (interquartile range, 30 to 61) in the rituximab group. This compared with 58 days (interquartile range, 26 to 79) in the group that had not received rituximab.

Key Findings: Treatment Effectiveness

The median follow-up was 15 months, with a range of 4 to 29 months. The results were striking across all three diseases.

All 15 patients successfully discontinued glucocorticoids (steroid medications) and all other immunosuppressive medications by the final follow-up. This means every patient achieved drug-free status.

The following sections describe the specific results for each disease group.

Results in Systemic Lupus Erythematosus

All eight patients with SLE met LLDAS criteria and achieved DORIS remission after 6 months. Their SLEDAI-2K score was zero after 6 months. A SLEDAI-2K score of zero means no measurable disease activity.

Analysis of BILAG status showed resolution of SLE in all major disease categories after 6 months. Long-term follow-up of up to 29 months showed that SLE disease activity remained absent in all eight patients. Their SLEDAI-2K score remained at zero.

Additional improvements were seen in laboratory markers:

• Anti-dsDNA antibodies (antibodies that attack the body's own DNA) disappeared and remained negative.
• Complement factor C3 levels (a protein involved in immune function) normalized.
• Proteinuria (protein in the urine, a sign of kidney damage) disappeared during the entire observation period.

One patient (Patient 4 with SLE) had a rebound of proteinuria 4 months after CAR T-cell therapy. A follow-up kidney biopsy did not reveal any signs of lupus nephritis. Instead, the biopsy showed concomitant podocytopathy (a condition affecting the kidney's filtering cells). This patient did not have a relapse and had only very mild proteinuria at the last follow-up (24 months).

Results in Idiopathic Inflammatory Myositis

All three patients with idiopathic inflammatory myositis had an ACR–EULAR major clinical response after 3 months. They also had normalization of creatine kinase levels. These responses were maintained over time.

Muscular function, as measured by the Manual Muscle Test–8 (MMT-8), normalized in all three patients. The MMT-8 score ranges from 0 to 150, with lower scores indicating weaker muscles. Extramuscular disease activity (disease activity outside the muscles) also ceased.

Results in Systemic Sclerosis

In the four patients with systemic sclerosis, global disease activity decreased in all four. Global disease activity was measured by the EUSTAR activity index. Skin activity, measured by the modified Rodnan skin score, also decreased in all four patients.

In the three patients with at least 6 months of follow-up, the median change in the EUSTAR activity index was −4.2 points (interquartile range, −4.7 to −2.3). The median change in the modified Rodnan skin score was −9 points (interquartile range, −17 to −7). Negative numbers indicate improvement.

Autoantibody and Vaccine Responses

The researchers analyzed autoantibodies (antibodies that attack the body's own tissues) in detail. In patients with SLE, autoantibodies against several targets disappeared. These targets included double-stranded DNA, single-stranded DNA, secondary necrotic cells, nucleosomes, and Smith protein.

Long-term analysis of autoantibodies in patients with SLE who had at least 1 year of follow-up (seven of eight patients) confirmed a sustained absence of SLE-specific autoantibodies.

Protective IgG responses to standard vaccines remained stable. These vaccines included tetanus, measles, mumps, rubella, varicella–zoster virus (the virus that causes chickenpox and shingles), and Epstein–Barr virus. This means the patients' ability to fight these infections was preserved.

Moderate decreases, but not loss, of antibodies against pneumococci (bacteria that can cause pneumonia) and SARS-CoV-2 (the virus that causes COVID-19) were noted during long-term observation.

Vaccinations given after CD19 CAR T-cell therapy and B-cell recovery led to a subsequent increase in antigen-specific IgG levels. These vaccinations included SARS-CoV-2 (in two patients), pneumococcus (in one patient), and tetanus (in two patients). This shows that the immune system could still respond to new vaccines after treatment.

B-Cell Recovery After Treatment

The researchers analyzed B-cell subsets at baseline, 4 months, and 12 months after CAR T-cell therapy. When B cells reappeared, they showed a naive B-cell phenotype. Naive B cells are immature B cells that have not yet encountered an antigen. This suggests the immune system was rebuilding itself from scratch.

In contrast, CD19+CD27+ memory B cells (B cells that remember past encounters with pathogens or self-tissues) were drastically reduced. There was a limited increase in these memory B cells between 4 and 12 months. This increase was predominantly seen in preswitched IgD+ CD27+ B cells.

CD27+CD38+ plasmablasts and SLE-associated activated CD11c+ memory B cells were not found after B-cell reconstitution. Immature CD38+ B cells, which indicate that B cells are being newly produced by the bone marrow, increased at 4 months and decreased thereafter.

These findings suggest that the treatment "reset" the B-cell compartment. The new B cells that emerged were primarily naive cells, not the autoreactive memory cells that drive autoimmune disease.

Safety and Side Effects

The safety profile was generally favorable. The most common side effect was cytokine release syndrome (CRS), a condition in which the immune system releases large amounts of inflammatory chemicals. Grade 1 CRS occurred in 10 patients. Grade 1 is the mildest form.

One patient had grade 2 cytokine release syndrome. One patient had grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS). One patient developed pneumonia that required hospitalization.

No cases of severe (grade 3 or higher) cytokine release syndrome or ICANS were reported.

The mean duration of B-cell aplasia (absence of B cells) was 112±47 days. This period of B-cell absence is expected with this treatment and is part of how it works.

What This Means for Patients

This study provides encouraging evidence that CD19 CAR T-cell therapy may offer a new treatment option for patients with severe autoimmune diseases. The most significant finding is that all 15 patients were able to stop all immunosuppressive medications. This is remarkable because these patients had severe, treatment-resistant disease before the therapy.

For patients with SLE, the treatment led to complete remission in all eight cases. Their disease activity scores dropped to zero, and their autoantibodies disappeared. For patients with idiopathic inflammatory myositis, muscle function normalized and disease activity stopped. For patients with systemic sclerosis, skin and global disease activity decreased.

The safety profile was also encouraging. Most side effects were mild. The cytokine release syndrome and neurotoxicity that can occur with CAR T-cell therapy were mostly low-grade and manageable.

Importantly, the immune system's ability to fight infections was largely preserved. Protective antibodies from previous vaccinations remained stable. Patients could still respond to new vaccinations after treatment.

However, patients should understand that this is a case series, not a randomized controlled trial. Case series describe what happened in a small group of patients. They cannot prove that the treatment caused the improvements, because there was no comparison group. Larger, controlled trials are needed to confirm these results.

Limitations of the Study

This study has several important limitations that patients and clinicians should consider.

• Small sample size: Only 15 patients were treated. This is too few to draw definitive conclusions about effectiveness or safety.
• No control group: All patients received the treatment. There was no comparison group receiving a placebo or standard treatment. This makes it difficult to know how much of the improvement was due to the treatment versus other factors.
• Short follow-up for some patients: The median follow-up was 15 months, with a range of 4 to 29 months. Longer follow-up is needed to determine whether remissions are sustained.
• Case series design: Case series are observational. They cannot establish cause and effect.
• Single-arm study: Without a comparison group, the researchers cannot calculate how much better this treatment is than existing options.
• Specialized treatment centers: The treatment was offered through an expanded-access program at specialized centers in Germany. Results may differ in other settings.

The authors note that the preliminary short-term effects in some of these patients were previously reported. This means some data may overlap with earlier publications.

Recommendations and Next Steps

The authors conclude that CD19 CAR T-cell transfer appeared to be feasible, safe, and effective in three different autoimmune diseases. They state that these results provide rationale for further controlled clinical trials.

Based on this study, the following next steps are recommended:

1. Conduct randomized controlled trials: Larger studies with control groups are needed to confirm the effectiveness of CD19 CAR T-cell therapy in autoimmune diseases.
2. Extend follow-up: Longer observation periods are needed to determine whether drug-free remission is sustained over many years.
3. Study different patient populations: Future research should include patients with less severe disease and from different geographic regions.
4. Compare with standard treatments: Head-to-head comparisons with existing therapies will help determine where CAR T-cell therapy fits in the treatment landscape.
5. Monitor long-term safety: Continued monitoring is needed to detect any delayed side effects or complications.

For patients with severe autoimmune diseases who have not responded to standard treatments, this study offers hope. However, CAR T-cell therapy is not yet approved for autoimmune diseases. It remains an investigational treatment available only through clinical trials or expanded-access programs.

Patients interested in this treatment should discuss it with their rheumatologist or immunologist. They should ask about eligibility for clinical trials and the potential risks and benefits.

Frequently Asked Questions

What is CD19 CAR T-cell therapy?

It is a treatment where a patient's own T cells are genetically modified to recognize and attack cells that carry a marker called CD19. This marker is found on a wide range of B cells and plasmablasts. By deeply depleting these cells, the treatment aims to reset the immune system and stop the autoimmune attack.

Who might be eligible for this treatment?

In the reported case series, patients had severe, progressive autoimmune disease and had failed at least two standard immunosuppressive treatments. The median number of prior treatments was five. The therapy was offered through an expanded-access program for critically ill patients. It is not yet approved for autoimmune diseases and is available only through clinical trials or expanded-access programs.

What were the results for lupus (SLE) in this case series?

All eight patients with SLE achieved remission and met low disease activity criteria after six months. Their disease activity scores dropped to zero. Anti-dsDNA antibodies disappeared and remained negative. Proteinuria disappeared during the observation period. These results were maintained for up to 29 months in follow-up.

What side effects occurred with CD19 CAR T-cell therapy?

The most common side effect was cytokine release syndrome (CRS). Grade 1 CRS occurred in 10 patients, and one patient had grade 2. One patient had grade 1 neurotoxicity (ICANS). One patient developed pneumonia requiring hospitalization. No severe CRS or ICANS occurred. B-cell absence lasted a mean of 112 days.

How long did patients go without immunosuppressive drugs?

All 15 patients successfully discontinued glucocorticoids and all other immunosuppressive medications by the final follow-up. This means every patient achieved drug-free status. The median follow-up was 15 months, with a range of 4 to 29 months. Longer follow-up is needed to determine whether these drug-free remissions are sustained over many years.

What does a SLEDAI-2K score of zero mean?

The SLEDAI-2K score measures lupus disease activity, ranging from 0 to 105, with higher scores indicating greater activity. A score of zero means no measurable disease activity. In the case series, all eight patients with SLE had a SLEDAI-2K score of zero after six months, and this remained at zero during long-term follow-up.

What are the limitations of this case series?

This was a small case series of 15 patients with no control group, so it cannot prove that the treatment caused the improvements. Follow-up was short for some patients (median 15 months). The treatment was given at specialized centers in Germany. Larger, controlled trials are needed to confirm the results and assess long-term safety.

I have severe lupus that hasn't responded to multiple treatments — when should I seek a second opinion about CAR T-cell therapy?

When standard immunosuppressive drugs have failed to control severe, progressive disease, a second opinion can clarify whether an investigational option such as CD19 CAR T-cell therapy is appropriate. In a 15-patient case series, all eight patients with SLE achieved drug-free remission, with disease activity scores falling to zero and autoantibodies disappearing, though this remains an investigational treatment available only through clinical trials or expanded-access programs. A second opinion can help confirm eligibility, review prior treatments, and weigh potential risks and benefits. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: CD19 CAR T-Cell Therapy in Autoimmune Disease A Case Series with Follow-up NEJM 2024

Authors: Fabian Müller, M.D., Jule Taubmann, M.D., Laura Bucci, M.D., Artur Wilhelm, Ph.D., Christina Bergmann, M.D., Simon Völkl, Ph.D., Michael Aigner, Ph.D., Tobias Rothe, Ph.D., Ioanna Minopoulou, M.D., Carlo Tur, M.D., Johannes Knitza, M.D., Soraya Kharboutli, M.D., Sascha Kretschmann, Ph.D., Ingrid Vasova, M.D., Silvia Spoerl, M.D., Hannah Reimann, Ph.D., Luis Munoz, M.D., Roman G. Gerlach, Ph.D., Simon Schäfer, Ph.D., Ricardo Grieshaber-Bouyer, M.D., Anne-Sophie Korganow, M.D., Dominique Farge-Bancel, M.D., Dimitrios Mougiakakos, M.D., Aline Bozec, Ph.D., Thomas Winkler, Ph.D., Gerhard Krönke, M.D., Andreas Mackensen, M.D., and Georg Schett, M.D.

Publication: The New England Journal of Medicine, February 22, 2024, Volume 390, Number 8, pages 687-700

DOI: 10.1056/NEJMoa2308917

Funding: Deutsche Forschungsgemeinschaft and others

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes only and should not replace consultation with a qualified healthcare provider. Patients should discuss any treatment decisions with their medical team.