CAR T cells are immune cells that have been specifically engineered to carry chimeric antigen receptors (CARs). These receptors enable the cells to selectively recognise and eliminate other cells displaying specific antigens [1]. CAR T-cell therapy can therefore be used in conditions where a particular cell population proliferates uncontrollably [1]. As a result, it has emerged as a highly successful treatment for B-cell-associated cancers [2].
Researchers are now investigating additional target antigens to expand CAR T-cell therapy to a broader range of conditions, including autoimmune diseases [1]. Many conventional therapies – including monoclonal antibodies – struggle to cross the blood-brain barrier (BBB) and reach the central nervous system (CNS) [1]. CAR T cells may overcome this limitation because they can penetrate tissues more effectively, making them a promising therapeutic option for multiple sclerosis (MS) [1].
A Living Therapy with a Promise of a One-Time Treatment
Professor Amit Bar-Or from the University of Pennsylvania says, “It is an exciting and growing field, with multiple types of engineered cells now being explored. Immune cells are taken out of the body, genetically modified outside the body, and then transfused back. They can either be returned to the same person – an approach known as autologous therapy – or taken from other donors and given to the patient, which is referred to as allogeneic therapy.”
“It is a living therapy,” Professor Manuel Friese of University of Hamburg tells us. “The goal is to modify these immune cells so that they can recognise and eliminate other cells. This approach has already been successfully applied in oncology, where malignant cell clones proliferate continuously. In autoimmune conditions, immune cells are persistently activated by the body’s own autoantigens. Many drugs originally developed for cancer therapy have already been adapted for use in autoimmune disease. For instance, anti-CD20 antibodies were first created to target malignant B cells, and they are now widely used to treat autoimmune disorders such as MS. A similar approach is now being explored with CAR T cells, which are programmed to eliminate the patient’s own B cells.”
Prof. Bar-Or explains, “The excitement in the treatment of MS began with anti-CD19 CAR T-cells, an engineered T cell designed to recognise and eliminate cells expressing CD19, including most B cells. These cells are thought to be critically involved in both the peripheral inflammation involved in MS relapses and in the inflammation within the CNS involved in progressive/neurodegenerative aspects of MS [3]. A profound depletion – and subsequent reconstitution or “reset” – of B cells induced by anti-CD19 CAR T cells has been observed in systemic lupus erythematosus (SLE), a multisystem autoimmune disease [4]. After a single infusion of these cells, lupus disease activity decreases and remains low even after B cells repopulate. This is a very important feature, as it avoids the need for long-lasting B cell depletion, which can increase infection risks. CAR T-cell therapy holds promise as a one-time treatment.”
In a study involving 15 adults with SLE, a single infusion of anti-CD19 CAR T cells induced a deep B-cell reset and led to long-lasting remission [5]. Some patients experienced a complete resolution of symptoms, while others showed a reduction in symptom severity. All patients could discontinue the therapy without experiencing relapses or disease worsening. Moreover, their B-cell populations fully reconstituted for up to two years, yet no relapses occurred [5]. Another study reports the effects of anti-CD19 CAR T cells in a 15-year-old patient with severe SLE and an end-stage renal disease. In this case, CAR T therapy was well tolerated and enabled the adolescent to stop haemodialysis [4].
Why CAR T Cells Offer Potential Advantages
What are the advantages of CAR T cells over antibodies? We ask Prof. Friese. “There are several advantages. First, CAR T cells persist in the body for a longer period and can eliminate B cells across multiple compartments. Unlike antibodies, which primarily target circulating B cells in the blood, CAR T cells are living drugs that can migrate throughout the body. They can even reach B cells that have become resident in certain tissues and cannot be depleted by antibodies, which may not access these sites. This is the case for the CNS in MS, where most antibodies do not effectively cross the BBB. Another important advantage is that they induce a deep depletion. So, B cells are not superficially depleted, they are almost completely depleted, not only in the blood but everywhere in the body.”
Possible Caveats in CAR T-Cell Therapy
“One of the caveats we are currently facing is that these living drugs stay in the body for a long time,” Prof. Friese explains. “However, in the few cases of lupus and MS treated so far with CAR T cells this does not appear to be an issue. After three to six months, these cells seem to disappear for various reasons – perhaps they die off or become exhausted.”
A limitation of this treatment is the potential risk of severe cytokine release syndrome (CRS), a serious inflammatory reaction that can cause fever, low blood pressure, and breathing difficulties [6]. In the study involving 15 adults with SLE cited earlier, 10 patients experienced mild CRS, one had moderate CRS, one developed mild neurotoxicity, and one experienced pneumonia that required hospitalisation [5].
Prof. Friese continues, “The idea was that this could be a treatment for patients who do not respond to existing therapies, but CAR T cells can come with quite some side effects. Because they are living T cells, they become strongly activated in the body when they encounter their target. This powerful activation can trigger the release of cytokines, which may potentially damage other organs or healthy cells. A massive cytokines surge has also been shown to alter brain function, and some patients may develop encephalopathy, becoming unresponsive or unable to think clearly. For this reason, clinicians have been very cautious in applying this therapy to people with MS. However, in Germany we have Individuelle Heilversuch, which refers to an individual therapeutic trial in which an off-license treatment is used as last-resort option for a life-threatening condition when no other therapy is available. Now overall we have treated five patients with MS with CAR-T cells and have not encountered any serious side effects.”
At the University Medical Centre Hamburg, the first antiCD19 CAR-T cell therapy on two individuals with progressive MS resulted in acceptable safety profiles. Researchers did not observe CAR-T cell-related neurological toxicity, but only low-grade CRS [7].
The safety of CAR T-cell therapies in MS still requires systematic long-term studies – particularly regarding the risk of neurotoxicity, given that the CNS is the primary target. It also remains uncertain whether a single CAR T-cell treatment can provide lasting control of autoimmunity while allowing healthy B-cell reconstitution [1].
Professor Bar-Or concludes, “It appears that the complications are not particularly common in the context of MS. Although the numbers are still relatively small, no major safety concerns have emerged so far, which is reassuring. Initial excitement was tempered by worries that applying this therapy in MS might be risky, but these early observations suggest no unusual or increased rate of complications compared with what has been seen in oncology. Overall, this is contributing to growing optimism that CAR T-cell therapy may hold real promise for MS. At the same time, there are practical and economic considerations. Cell therapies are far more complex than antibody treatments: they require specialised centred to generate and infuse these cells. Issues of scalability, accessibility, and cost remain significant challenges. For now, it will be crucial for the field to continue evaluating safety and to obtain proof of principle that this approach can add value to the current treatment landscape for MS. Next-generation CAR T therapies that are easier to use, more practical, less expensive, and – if they also prove effective and safe – could ultimately become a highly meaningful addition to MS treatment options. It is, in many ways, an exciting moment for the field.”
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Written by Stefania de Vito
Special thanks to Professor Manuel Friese (University of Hamburg) and Professor Amit Bar-Or (University of Pennsylvania) for their insights.
References
[1] Pfeffer LK et al. Brain 2025; 148.3: 723-736.
[2] Schett G, Mackensen A, & Mougiakakos D The Lancet 2023; 402(10416): 2034-2044.
[3] Comi G et al. Ann. Neurol. 2021; 89(1): 13-23.
[4] Krickau T et al. The Lancet 2024; 403.10437: 1627-1630.
[5] Müller F et al. (2024). NEJM 2024; 390(8): 687-700.
[6] Giavridis T et al. Nat. Med. 2018; 24(6): 731-738.
[7] Fischbach F et al. Med 2024; 5(6): 550-558.