EULAR 2024 (VIENNA)—In 2022, Georg Schett, MD, head of the Department of Medicine 3 (Rheumatology and Immunology) of the Friedrich-Alexander University Erlangen-Nürnberg, Germany, and colleagues electrified the medical world with their article describing anti-CD19 CAR-T cell therapy in five patients with refractory systemic lupus erythematosus (SLE), published in Nature Medicine.1 Since that time, the rheumatology field has been abuzz about this potentially paradigm-shifting form of treatment.
At EULAR 2024, Dr. Schett’s presentation, What Is New: CAR-T Cells to Treat Rheumatic and Musculoskeletal Diseases, explained the cellular therapy revolution currently taking place.
- An antibody-like extracellular domain capable of recognizing a specific antigen and an intracellular portion with a co-stimulatory domain (either CD28 or 4-1BB); and
- A second domain that shows the T cell receptor signal.
When the CAR comes into contact with the antigen, it’s designed to recognize that intracellular domains are activated, and the T cell is stimulated to destroy its target. Dr. Schett explained that CAR-T cells are “living drugs” that act like serial killers, going from one cell to another terminating their cellular victims anywhere they are found throughout the body.
CAR-T cells have historically been created using an autologous procedure, meaning the T cells are harvested from the patient, modified in a lab and then reinfused into that patient. There are now attempts to use an allogeneic procedure, during which T cells obtained from a single healthy donor are subsequently gene edited to reduce antigenicity, thus creating off-the-shelf CAR-T cell products that can be used in different patients. Dr. Schett further noted that, in the not-too-distant future, we may have an in vivo procedure, during which the transduction process can be done within the body of the patient without needing to harvest and reinfuse the cells.
Background
Dr. Schett
Dr. Schett noted that CAR-T cell treatment is not new to medicine. In the 2010s, the first patients to receive such treatment were adults with severe, relapsing hematologic malignancies.2
In 2012, a 6-year-old named Emily Whitehead became the first pediatric patient to be treated with CAR-T cell therapy for her acute lymphoblastic leukemia. In 2022, she celebrated 10 years of disease-free survival.3 An incredible—and important—aspect of Emily’s story is that, during her treatment, she experienced the complication of cytokine release syndrome—a large, rapid release of cytokines created a life-threatening wave of inflammation. Through the inspired thinking of her medical team, tocilizumab, an inhibitor of interleukin (IL) 6, was used to treat this complication, thereby saving her life and CAR-T cell treatment from the waste basket of medical history.
A Case Study
In 2021, Dr. Schett and colleagues were caring for a young woman with severe SLE with manifestations that included renal, cardiac and pulmonary involvement. She had cycled through many SLE treatments, including B cell depleting therapy. Despite all these efforts, she experienced progression of her class IV lupus nephritis and was headed for hemodialysis.1
Given her limited options, the medical team and patient decided to try CAR-T cell therapy using an autologous procedure. The patient’s peripheral blood, containing a mixture of T cells, B cells and monocytes, was collected and enriched to obtain a pure population of about 100 million T cells. These cells were transfected with CAR-containing lentivirus and expanded to create 1 billion CAR-T cells. Of these, 50 million CAR-T cells were infused into the patient. From three to nine days after the infusion, the CAR-T cells increased from 0.3% of her total T cells to 27%.
The subsequent effects on the patient’s immune system were dramatic: Her B cells became undetectable, her anti-double-stranded DNA (dsDNA) antibody seroconverted from positive to negative, her complement 3 (C3) level normalized, and her proteinuria improved. By day 30 after treatment, the patient essentially experienced a complete resolution of her disease. More than three years after treatment, the patient appears to be in complete clinical remission, with no signs of active disease and no need for immunosuppressive medications.
Current Findings
In February 2024, Dr. Schett and his colleagues further advanced our knowledge in this field, publishing an article in The New England Journal of Medicine. Their work described the results of CAR-T cell therapy in eight patients with SLE, three patients with idiopathic inflammatory myositis and four patients with systemic sclerosis (see our summary and an interview with one of the authors).4
These patients were followed for a median of 15 months after a single infusion of CD19 CAR-T cells and preconditioning with fludarabine and cyclophosphamide. Over this period, all patients with SLE achieved Definition of Remission in SLE (DORIS) remission; all patients with myositis had an ACR/EULAR major clinical response and normalization of creatine kinase (CK) level; and all patients with systemic sclerosis had a decrease in the European Scleroderma Trials and Research Group (EUSTAR) activity index score. Additionally, all patients were able to stop immunosuppressive therapy.4
The authors did report that grade 1 cytokine release syndrome occurred in 10 patients. Additionally, three patients required hospitalization: one for grade 2 cytokine release syndrome, one for immune effector cell-associated neurotoxicity syndrome (ICANS) and one for pneumonia.4
Dr. Schett noted that potential therapeutic complications, such as cytokine release syndrome and ICANS, must be kept in mind, along with a boxed warning from the U.S. Food & Drug Administration on potential T cell malignancies in patients receiving CAR-T cell immunotherapies.5
The implications of these findings in real-life patients are provocative. Perhaps, Dr. Schett said, we will have the opportunity to move from traditional autoimmune disease management (i.e., finding a treatment regimen that suppresses disease activity and continuing that regimen indefinitely) to a visionary scenario in which a short-term treatment results in long-term absence of disease without the need for continued treatment.
In Sum
Much work remains to be done in the field, but Dr. Schett’s presentation was a fascinating and insightful imagining of what the future may look like for a host of patients with severe, refractory rheumatic diseases. If the positive results of CAR-T cell therapy can be replicated in larger groups of patients with autoimmune disease, such treatments may change the face of rheumatic care as we know it.
Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
Resource
“CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus”: https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42784
References
- Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124–2132.
- Mitra A, Barua A, Huang L, et al. From bench to bedside: The history and progress of CAR-T cell therapy. Front Immunol. 2023 May 15;14:1188049.
- Emily Whitehead, first pediatric patient to receive CAR T cell therapy, celebrates cure 10 years later. Philadelphia Children’s Hospital. 2022 May 10.
- Müller F, Taubmann J, Bucci L. CD19 CAR T cell therapy in autoimmune disease—a case series with follow-up. N Engl J Med. 2024 Feb 22;390(8):687–700.
- FDA requires boxed warning for T cell malignancies following treatment with BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies [news release]. U.S. Food and Drug Administration. 2024 Apr 18.
