Chimeric antigen receptor T-cell therapy for stiff-person syndrome: bridging innovation and clinical challenges in neuroimmunology

Abstract

Chimeric antigen receptor T-cells (CAR T-cells) have revolutionized the treatment of hematologic malignancies and are now being explored in autoimmune diseases, including neuroimmunological disorders. The first clinical applications of CAR T-cell therapy for autoimmune diseases have demonstrated promising efficacy, particularly in systemic lupus erythematosus and myasthenia gravis. While CAR T-cell therapy can induce profound B-cell depletion, leading to durable remission, concerns remain regarding cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. However, neuroimmunological conditions with lower target cell burdens may carry a reduced risk of these adverse events. Recent evidence suggests CAR T-cells could offer a transformative approach for stiff-person syndrome (SPS), a rare but debilitating autoimmune neurological disorder characterized by muscle rigidity and spasms. The first reported case of anti-CD19 CAR T-cell therapy in a treatment-refractory SPS patient resulted in substantial clinical improvement, including increased mobility and reduced dependence on symptomatic medication. A newly launched phase II clinical trial (NCT06588491) aims to further evaluate the safety and efficacy of anti-CD19 CAR T-cell therapy in SPS. In this review, we examine the current evidence supporting the use of CAR T-cells in neuroimmunological conditions, discuss the clinical picture and pathophysiological processes associated with stiff person spectrum disorders (SPSD), and elaborate on perspectives and limitations of CAR T-cell therapy in SPSD and beyond.

Plain language summary

CAR T-cells for stiff-person syndrome

CAR T-cell therapy is an innovative treatment originally developed for blood cancers but now being tested for autoimmune diseases. These genetically modified immune cells can precisely target harmful B-cells, potentially offering long-term remission. The first reported use of CAR T-cells in a patient with Stiff-Person Syndrome showed significant improvements in mobility and symptoms without severe side effects. A new clinical trial is investigating whether this therapy could become a standard treatment for this rare neurological disorder.

Keywords

CAR CAR-T cell SPS CD19 GAD SPSD PERM

Chimeric antigen receptor T-cells: Overview

Chimeric antigen receptor T-cells (CAR T-cells) represent a groundbreaking innovation in immunotherapy, originally designed to target cancer but increasingly applied to a broader range of diseases, including neuroimmunological conditions.¹ The first clinical applications of CAR T-cell therapy in hematologic patients took place in the early 2010s. A landmark case occurred in 2012 when two children with acute lymphoblastic leukemia (ALL) were successfully treated with CAR T-cells,² garnering global attention. The first regulatory approval of CAR T-cell therapy came in 2017 when the U.S. FDA authorized Tisagenlecleucel (Kymriah, Novartis, Basel, Switzerland) for refractory or relapsed ALL in patients up to 25 years old, and later for diffuse large B-cell lymphoma.^3,4 This marked a turning point in the treatment of hematologic malignancies⁵ and the beginning of a new era in immunotherapy.

By combining genetic engineering with the cytotoxic capabilities of T-cells, CAR T-cells enable precise and potent targeting of specific antigens, offering new therapeutic possibilities for disorders with otherwise limited treatment options. By equipping T-cells with synthetic receptors, CAR T-cells can identify and eliminate specific target cells with remarkable precision, bypassing the limitations of conventional treatments.¹ The core structure of CAR T-cells integrates three essential components (Figure 1): The extracellular antigen-binding domain, derived from antibody fragments, allows the modified T-cells to recognize and bind to target antigens without relying on the major histocompatibility complex.⁶ This specificity is critical for their function. A transmembrane domain anchors the receptor to the cell membrane, providing the necessary stability for optimal performance. The intracellular signaling domain, incorporating activation and costimulatory molecules, ensures that CAR T-cells are not only activated upon antigen recognition but also sustain their activity to deliver a robust therapeutic response. The activation of CAR T-cells leads to the release of cytotoxic molecules such as perforin and granzyme, which leads to the depletion of the target cells.¹ Over time, the design of CAR T-cells has undergone significant refinements. Early versions included only basic activation domains, which limited their efficacy and persistence. Advances in design introduced costimulatory signals, leading to the development of second-generation CAR T-cells with improved functionality.⁶ Subsequent iterations, integrating multiple signaling pathways or inducible cytokine production, have further enhanced their therapeutic potential, enabling them to address more complex disease mechanisms. Second-generation constructs can now be used with high reliability. Further developments of CAR T-cell therapy are ongoing, for example, bispecific/dual-targeting CAR T-cells⁷ and split-signal CAR constructs.⁸ Bispecific CARs target two antigens simultaneously improving efficacy and tumor escape in hematological malignancies. Split-signal CARs separate activation and co-stimulation signals, offering more controlled immune responses and minimizing toxicities.

Figure 1.

Schematic structure of a CAR. The figure depicts the components of a CAR with an extracellular antigen binding domain, a transmembrane domain, and the intracellular signaling domain comprising a costimulatory domain and a T-cell activation domain.

A well-known consequence and potentially clinical relevant adverse event associated with the application of CAR T-cells is the development of a cytokine release syndrome (CRS) or neurotoxic effects termed immune effector cell-associated neurotoxicity syndrome (ICANS), which needs special attention in the early phase after CAR T-cell application.⁹ In 133 adults with refractory B-cell malignancies, including ALL, neurologic adverse events after CD19 CAR T-cell therapy were linked to high CAR T-cell doses, CRS, and preexisting neurologic conditions. Severe cases showed endothelial activation, blood–brain barrier (BBB) disruption, and elevated cytokines like interferon-gamma, identifying endothelial dysfunction as a key risk factor.⁹ Management of CRS includes antipyretics and glucocorticoids as well as the use of anti-IL6R directed antibodies such as tocilizumab to reduce the activation of myeloid cells, involved in CRS pathophysiology.¹⁰ Of note, the amount of cells to be depleted by CAR T-cells, is a key driver of the risk to develop severe CRS.¹¹ This is why neuroimmunological conditions with lower amounts of target cells are postulated to be associated with a potentially lower risk of both CRS and ICANS. Side effects of CAR T-cell therapy may be further reduced using RNA-based CAR T-cell therapies¹² by enabling only transient CAR gene integration in T-cells, thereby avoiding uncontrolled CAR T-cell proliferation and minimizing the risk of mutagenesis.

Aims and methods

A comprehensive literature search was conducted in PubMed using the keywords “stiff person syndrome,” “SPS,” and “chimeric antigen receptor T-cell therapy,” “CAR T-cell therapy” to identify relevant studies published. To identify ongoing clinical trials, a search was conducted on ClinicalTrials.gov using the terms “stiff person syndrome (SPS)” and “CAR T-cell therapy.”

CAR T-cells in neuroimmunology

The first use in patients with immunological diseases was conducted in patients with rheumatological disorders. Five patients with refractory systemic lupus erythematosus (SLE) achieved DORIS remission and drug-free status within 3 months of anti-CD19 CAR T-cell therapy.¹³ Remission persisted over a median follow-up of 8 months, with treatment showing high efficacy, deep B-cell depletion, and mild side effects.¹³ In a long-term follow-up in 15 patients with severe autoimmune diseases, including SLE, idiopathic inflammatory myositis, and systemic sclerosis, all patients achieved clinical remission or significant disease activity reduction over a median follow-up of 15 months, with immunosuppressive therapy discontinued in all cases. The longest reported relapse-free remission to date for SLE following CAR T-cell therapy is 29 months.¹⁴ The treatment was generally safe, with mild CRS in most patients and one serious infection.¹⁴

In neuroimmunology, CAR T-cells are emerging as a promising tool to modulate immune responses and counteract pathological processes.^15–19 Their application extends to autoimmune disorders and inflammatory conditions of the nervous system, where they can target aberrant immune cells or molecular mediators responsible for disease progression. A phase Ib/IIa trial evaluated Descartes-08, an RNA-based anti-B cell maturation antigen (BCMA) CAR T-cell therapy, in 14 adults with generalized myasthenia gravis (MG).¹² Without lymphodepletion, the therapy was well tolerated, showing no CRS, neurotoxicity, or dose-limiting toxicity. Participants experienced significant improvements in disease severity scales, with effects lasting up to 9 months. In neurological autoimmune disorders, DNA-based anti-CD19 CAR T-cell therapy has been used in patients with MG,¹⁷ Lambert–Eaton syndrome with/without concomitant MG,¹⁵ neuromyelitis optica,²⁰ Diacylglycerol lipase alpha antibody-associated autoimmune encephalitis,²¹ MOG antibody-associated disease,²² and multiple sclerosis (MS).¹⁶ In MS, CD19 CAR T-cell therapy was administered to two patients with progressive MS, showing an acceptable safety profile with no signs of neurotoxicity, including ICANS, despite CAR T-cell presence in cerebrospinal fluid.¹⁶ Notably, one patient demonstrated reduction in intrathecal antibodies over several months, indicating CAR T-cell effects on CD19⁺ target cells in the CNS.¹⁶ Another compelling example is the potential role of CAR T-cells in treating stiff-person syndrome (SPS), a rare autoimmune neurological disorder characterized by muscle rigidity and spasms.

Clinical presentation of SPS and subforms

First described in 1956 by Moersch and Woltman,²³ SPS is characterized by muscle stiffness with concurrent spasms, often leading to a pronounced gait impairment, along with an exaggerated startle response. Additionally, task-specific phobias of performing usual activities may be present.²⁴ Electromyography typically shows evidence of continuous motor unit activity at rest with concurrent firing of agonistic and antagonistic muscles.^25,26 Clinical presentations have traditionally been categorized into “classic” SPS, stiff limb syndrome, stiff person plus syndrome (the “classic” SPS along with additional signs such as cerebellar ataxia), acquired hyperekplexia and progressive encephalomyelitis with rigidity and myoclonus (PERM). These subforms are summarized as stiff person spectrum disorders (SPSD).²⁷

Autoantibodies in SPS – Pathophysiological implications

All SPSD subtypes have two pathophysiological mechanisms in common: First, disturbance of reciprocal GABAergic inhibition which causes spasms and stiffness. Second, autoimmunity with detection of autoantibodies targeting inhibitory synapses. The most common are antibodies to the glutamic acid decarboxylase 65 (GAD65, GAD), to the synaptic endocytosis protein amphiphysin, and to the glycine receptor (GlyR). In few cases, autoantibodies to GABA A receptor, GABA A Receptor associated protein, dipeptidyl peptidase-like protein 6 (DPPX), or gephyrin may be detected (Figure 2).

Figure 2.

Antigen targets in SPSDs. Intracellular antigen targets include GAD, Gephyrin, GABARAP, and amphiphysin. In contrast to the other intracellular antigens, amphiphysin (shown in yellow) may be accessible to autoantibodies due to its involvement in vesicle endocytosis. Extracellular target antigens are GABA A receptors, GlyR, and dipeptidyl peptidase-like protein (DPPX). GAD, GlyR, and amphiphysin are the most common target antigens in SPSDs.

SPS with antibodies to GAD

Autoantibodies to GAD are by far the most frequently detected in SPSD but can also occur along a spectrum of nonneurological autoimmune disorders such as diabetes mellitus type 1, vitiligo, pernicious anemia, and thyroid dysfunction.²⁸ If GAD antibody titers are <10,000 IU/ml, it is therefore recommended to test for intrathecal GAD antibody production.²⁵ A genetic predisposition of SPSD with GAD antibodies is assumed.²⁹ As GAD is the rate-limiting enzyme of GABA synthesis, it was hypothesized that GAD antibodies may directly cause a reduction of GABA. However, due to the intracellular location, the pathogenic relevance of GAD antibodies is debated unlikely.²⁵ So far, evidence of GAD antibody internalization is still missing, and experimental data are inconsistent and do largely not support pathogenicity of GAD antibodies.^30–35 Therefore, alternative pathophysiological processes, such as T-cell mediated neuronal damage are important in GAD antibody-associated immunopathology including temporal lobe epilepsy and SPS.^25,36

SPS with GlyR antibodies

The most common SPSD phenotype associated with GlyR antibodies is PERM, while milder and more focal variants can occur. In around 9% of cases, there is an underlying paraneoplastic neurological syndrome (PNS), most frequently associated with thymoma. GlyR are expressed predominantly in the cerebellum, brainstem, and spinal cord, where glycine is a potent inhibitory transmitter. GlyR antibodies directly lead to internalization of the receptor by binding the extracellular domain and therefore reduce inhibitory neurotransmission.^37–41 Moreover, GlyR antibodies may also induce direct effects on receptor function.⁴² Thus, different to antibodies against GAD65, GlyR antibodies are regarded as pathogenic as they directly cause disease symptoms.

SPS with antibodies against amphiphysin—Paraneoplastic SPS

SPS with antibodies to amphiphysin is mostly a paraneoplastic variant, as the antibodies are classified as “high-risk” antibodies for PNS with a strong association to small cell lung cancer and breast cancer.⁴³ Passive-transfer of amphiphysin antibodies was able to induce typical SPS symptoms in rat models.^44,45 As a central element in clathrin-mediated endocytosis, amphiphysin is responsible for GABA-associated inhibitory activity at the synapses.⁴⁵ As amphiphysin antibodies disturb clathrin-mediated endocytosis, GABA levels in the spinal cord are reduced.⁴⁶ Although amphiphysin is located intracellularly, it may become accessible to antibodies during vesicle recycling with internalization via an epitope-specific mechanism.⁴⁷

Treatment strategies in SPSD

Treatment of SPSD involves both immunotherapy as well as symptomatic treatment, taken into account the considerations for first- and second-line immunotherapy for autoimmune encephalitides.^48,49 The response to immunotherapy varies between the SPSD subtypes and critically depends on the type of associated autoantibody (intracellular or membrane-surface antigen, paraneoplastic or sporadic variant). Moreover, various factors play a part in potentially predicting the response, such as timepoint of initiation, age and the grade of disability at treatment start.

Commonly, the first-line treatment for GAD-associated SPS are intravenous immunoglobulins (IVIg), but IVIg maintenance therapy may provide long-term benefits in only approximately two-third of patients.^50,51 Plasma exchange and intravenous methylprednisolone are possible alternatives, but efficacy is heterogeneous and long-term side effects of corticosteroids are limiting, especially if diabetes mellitus is present.^52–54 Most experience for second-line immunotherapy exists for rituximab, which can be useful in cases with active relapsing disease course. However, a placebo-controlled clinical trial evaluating rituximab in SPS could not meet its primary endpoint of clinical improvement.⁵⁵ In general, immunotherapy with other second-line agents such as azathioprine, mycophenolate mofetil, and cyclophosphamide have not shown sufficient benefit.^56,57 In one refractory case, administration of bortezomib showed promising clinical improvement.⁵⁸ Autologous hematopoietic stem cell transplantation can be a last option in refractory SPS patients with ongoing inflammatory activity^59,60 but should be evaluated carefully, as serious adverse events can occur. Notably, a prospective study was prematurely stopped due to lack of therapeutic benefit.⁶¹

In the majority of cases, first- and second-line immunotherapy can improve symptoms in anti-GlyR SPS meaningfully, while there is a high chance for relapses, even years after initial symptom onset.³⁷ Notably, in PERM early treatment initiation is essential as irreversible neuronal damage may occur, and the disease course may be fatal.⁶²

While immunotherapy can, at least, stabilize the disease course in most cases, the search, and possibly the treatment, of the underlying malignancy is of central importance in amphiphysin-associated SPS. Concomitant presence of other antibodies, mainly CRMP5- and/or ANNA1-antibodies, are associated with poorer treatment response.^63,64

In all subtypes of SPSD, immunotherapy often leads to partial improvement or stabilization of symptoms. However, profound improvement is rare, and patients depend on additional symptomatic treatment. To reduce muscle tone and painful spasms, oral benzodiazepines, for example, clonazepam or diazepam, are used. In more severe cases, intrathecal baclofen injections may be needed. Additionally, nonpharmacological interventions, for example, physiotherapy or behavioral therapy, are of great importance. Nonetheless, the majority of SPSD patients still suffer from relevant impairment underlining the need of new therapeutic approaches to address a medical need in this rare neuroimmunological disorder.

First clinical use of CAR T-cells in SPS

A recent case study has demonstrated the successful use of anti-CD19 CAR T-cells in a 69-year-old female patient with treatment-refractory SPS.¹⁸ This patient, who had previously experienced limited benefits from conventional immunotherapies such as azathioprine, rituximab, and bortezomib, exhibited significant clinical improvements following a single infusion of autologous anti-CD19 CAR T-cells (KYV-101). Within 3 months, the patient’s gait and walking speed improved dramatically, daily uninterrupted walking distance increased from less than 50 m to over 6 km, and GABAergic medication use decreased by 40%. Importantly, the therapy was well tolerated, with only low-grade CRS observed, highlighting its safety profile.¹⁸ A significant reduction in anti-GAD65 antibody titers was observed, which decreased from 1:3200 at baseline to 1:320 by day 144 post-treatment. This suggests that CAR T-cells effectively target and deplete CD19-positive B-cells, including pathogenic plasma cells and plasmablasts. The patient has now been followed up for 22 months. During this period, the patient did not require any immunotherapy, including IVIg and had no unplanned hospital admissions. The use of diazepam could be reduced to 10 mg per day, and the uninterrupted walking distance remained at 4–6 km using a walker. After rehabilitation, she was able to walk several tens of meters unaided and, most importantly, the patient had no side effects, including infections. Despite the remarkable therapeutic benefits, certain challenges and limitations persist. The patient displayed residual stiffness,¹⁸ potentially attributable to irreversible neurodegeneration and astrogliosis, as observed in severe, long-standing SPS cases.⁶² This underscores the importance of early intervention to prevent permanent damage.

Clinical trial

A recent multicenter, phase II clinical trial (NCT06588491) is investigating the safety and efficacy of anti-CD19 CAR T-cell therapy for treating SPSD. The trial plans to enroll up to 25 participants, of whom at least 20 must be ambulatory at the time of inclusion. The primary endpoint focuses on the safety of the therapy, specifically assessing the incidence and severity of adverse events, while secondary endpoints include reductions in stiffness scores, improvements in mobility and quality of life, and a decrease in antibody titers such as anti-GAD65 (Table 1).

Table 1.

Summary table for clinical trial NCT06588491.

Category	Details
Study objective	Assess the safety and efficacy of anti-CD19 CAR T-cell therapy in SPS.
Primary endpoint	• Change in the T25-FW from baseline • Incidence of adverse events and laboratory abnormalities
Secondary endpoints	• Reduction in stiffness scores (e.g., stiffness index) • Improvements in mobility and quality of life • Change in modified Rankin Scale • Reduction in antibody titers (e.g., anti-GAD65) • 6-min walking test • Immunological measurements (levels of CAR T cells and B cells in the blood)
Planned enrollment	Up to 25 participants (at least 20 must be ambulatory at the time of inclusion).
Study duration	Primary endpoint up to 16 weeks Comprehensive follow-up for long-term safety and efficacy up to 12 months
Key inclusion criteria	Diagnosis of SPS with specific clinical features: • Limb and axial rigidity, especially in the thoracolumbar region. • Continuous agonist and antagonist muscle contraction (clinical/electrophysiological evidence). • Spasms triggered by noise, touch, or emotion. • High titer anti-GAD65 or antiglycine antibodies (or CSF positivity for GAD65 if peripheral levels are borderline). • Stiffness index ⩾2. • Inadequate response to at least one immunomodulatory therapy. • At least 20 participants must be ambulatory.
Key exclusion criteria	• Bedridden for more than 3 months. • History of specific neurological conditions unrelated to SPS (e.g., stroke, seizure, Parkinson’s disease, PML). • Cardiac ejection fraction ⩽40%. • CNS or spinal cord tumors, inherited progressive CNS disorders, or sarcoidosis.

CAR, chimeric antigen receptor; GAD65, glutamic acid decarboxylase 65; SPS, Stiff-Person syndrome; T25-FW, timed 25-foot walk.

Participants must meet specific inclusion criteria, including a confirmed diagnosis of SPS with hallmark symptoms such as limb and axial rigidity, continuous muscle contractions, and spasms triggered by stimuli. They must exhibit high titers of anti-GAD65 or antiglycine antibodies or show cerebrospinal fluid positivity for GAD65 if peripheral levels are borderline. Additionally, eligible patients must have a stiffness index of ⩾2 and active symptoms unresponsive to at least one prior immunomodulatory therapy. Key exclusion criteria include bedridden status for more than 3 months, significant comorbidities such as cardiac dysfunction (ejection fraction ⩽40%), or unrelated neurological conditions such as stroke or Parkinson’s disease. The primary outcome is the change in the Timed 25-Foot Walk up to 16 weeks. This trial will be an important step forward addressing a significant unmet clinical need.

Discussion

A critical immunological limitation in the current understanding of anti-CD19 CAR T-cell therapy for SPS lies in the diversity of antibodies with different pathophysiological relevance and in the incomplete characterization of T-cell involvement in the disease. There is evidence for pathogenicity of GlyR and amphiphysin antibodies in SPSD. However, since GAD antibodies target an intracellular antigen, the pathogenicity of GAD antibodies remains unclear and is rather unlikely.^25,31 The role of T-cells, particularly of cytotoxic subsets, in directly attacking GABAergic interneurons or amplifying or moderating the autoimmune response is likely contributing to GAD antibody mediated diseases. This was recently demonstrated in autopsies in patients suffering from autoimmune-mediated temporal lobe epilepsy associated with antibodies to GAD.³⁶

Anti-CD19 CAR T-cell therapy targets B-cells and plasmablasts, effectively depleting peripheral B-cell populations and reducing antibody titers. Moreover, CD19 CAR T-cell therapy may indirectly modulate T-cell activity by affecting B-cell driven T-cell activation and priming. The profound depletion of B-cells might disrupt the broader immune regulatory network, potentially altering T-cell function or reactivity. This could either be beneficial, by reducing T-cell priming and activation in response to B-cell antigens, or detrimental, by destabilizing immune homeostasis and leading to unforeseen effects. Given the unclear pathogenic relevance of GAD antibodies, improvement of the GAD SPS patient after anti-CD19 CAR T-cell treatment may rather be explained by reduction of T-cell activation upon B-cell depletion similar to the intriguingly beneficial effects of CD19 CAR T-cell driven B-cell depletion in patients with MS.¹⁶

Of note, the mechanism by which CAR T-cells exert their therapeutic effect within the CNS remains unclear. There is early evidence that these cells penetrate the BBB with reduction in intrathecal antibodies.¹⁶ Unlike CNS malignancies such as glioblastoma, where partial disruption of the BBB may facilitate CAR T-cell penetration into the tumor, the BBB is often intact in neuroimmunological disorders, potentially limiting such access. It is thus uncertain whether CAR T-cells penetrate the BBB in sufficient numbers to directly impact intrathecal autoimmune processes with long-term effects or whether peripheral depletion of B-cells is sufficient to modulate CNS immunity. This uncertainty underscores the need for studies investigating the trafficking, persistence, and functional activity of CAR T-cells within the CNS environment.

So far, no cases have been published using CAR T-cells in SPS associated with GlyR or amphiphysin antibodies. GlyR antibodies are considered to be directly pathogenic, and the disease course is frequently more severe as GlyR SPS often occurs as PERM. Therefore, a CD19 CAR-T approach with deep depletion of B-cells and plasmablasts seems to be promising similar to other diseases with pathogenic autoantibodies mediating the disease, for example, MG,¹⁷ or in further antibody-mediated CNS disorders, for example, autoimmune encephalitis with antibodies to neuronal surface antigens.^21,65 Moreover, other CARs targeting, for example, BCMA on plasma cells or plasma blasts could also be a valuable option to efficiently reduce pathogenic antibodies as it has been shown in aquaporin-4 positive NMO.⁶⁶ However, as anti-BCMA CAR T-cells reduce vaccine titers and overall IgG to a higher degree than anti-CD19 CAR T-cells, side effects such as infections may be more common. In general, as autopsy results indicate irreversible destruction of the spinal cord,⁶² we suggest that rather early escalation of immunotherapy, for example, using CD19 CAR T-cell therapy would be necessary to avoid persisting deficits in GlyR SPS.

In contrast to GlyR SPS, we speculate that treating amphiphysin antibody-positive SPS with a conventional CAR T-cell approach (i.e., including prior lymphodepletion) may increase the risk of tumor development or tumor progression. Even if no tumor has been detected when SPS is diagnosed, lymphodepletion may impair antitumor immunity and facilitate tumor growth. Thus, if a CAR T-cell approach is considered in paraneoplastic SPS, strategies which may circumvent lymphodepletion, for example, mRNA based-CAR T-cell therapy¹² or even chimeric autoantigen receptor (CAAR) T-cell therapy should be preferred over conventional CAR T-cell therapy in future. CAARs are engineered receptors introduced into T-cells that mimic the autoantigens targeted by the immune system in specific autoimmune diseases. When infused into the patient, CAAR T-cells bind and specifically deplete harmful B-cells that recognize the autoantigen. First preclinical data have shown that a CAAR approach may be feasible in conditions where the target antigen region is clearly defined, for example, in NMDA receptor encephalitis.⁶⁷ Still, questions remain on the effectiveness and if circulating pathogenic antibodies may affect the CAAR binding sites.

Similar to other paraneoplastic disorders, escalation of immunotherapy should be performed with caution but may be required due to the severity of neurological symptoms.

Summary

In conclusion, while CAR T-cell therapy offers a promising approach to targeting B-cell-driven mechanisms, the potential involvement of T-cells in the disease process in SPSD and their modulation by this therapy remain poorly understood. Future research should aim to elucidate the role of T-cells in SPSD pathogenesis, in particular in SPS associated with GAD antibodies and investigate how CAR T-cell therapy influences broader immune dynamics, particularly in the CNS. Addressing these questions will be essential to refining this therapeutic strategy and expanding its applicability. The ability to achieve substantial clinical and immunological improvements in a refractory case of SPS underscores the potential of this approach as a paradigm-shifting treatment. However, controlled clinical trials are required to validate these results, refine patient selection criteria, and address outstanding questions regarding long-term safety and efficacy. As the field advances, CAR T-cell therapy may emerge as a cornerstone in the management of neuroimmunological diseases, offering hope to patients with conditions previously deemed untreatable.

Footnotes

Acknowledgements

We would like to thank Dr Anja Strauß for designing Figure 2. Figures 1 and were created with BioRender.com.

Declarations

ORCID iDs

Jeremias Motte

Ralf Gold

Simon Faissner

References

Haghikia

Schett

Mougiakakos

B cell-targeting chimeric antigen receptor T cells as an emerging therapy in neuroimmunological diseases. Lancet Neurol 2024; 23(6): 615–624.

Grupp

Kalos

Barrett

, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368(16): 1509–1518.

Schuster

Bishop

Tam

, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019; 380(1): 45–56.

Maude

Laetsch

Buechner

, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018; 378(5): 439–448.

Gardner

Shah

NN.

CAR T-cells for cure in pediatric B-ALL. J Clin Oncol 2023; 41(9): 1646–1648.

Mougiakakos

Sengupta

Gold

, et al. Successful generation of fully human, second generation, anti-CD19 CAR T cells for clinical use in patients with diverse autoimmune disorders. Cytotherapy 2025; 27(2): 236–246.

de Oliveira Canedo

Roddie

Amrolia

. Dual-targeting CAR T cells for B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma. Blood Adv 2025; 9(4): 704–721.

Shi

Zhao

, et al. Split-design approach enhances the therapeutic efficacy of ligand-based CAR-T cells against multiple B-cell malignancies. Nat Commun 2024; 15(1): 9751.

Gust

Hay

Hanafi

, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 2017; 7(12): 1404–1419.

10.

Jain

Smith

Shah

NN.

How I treat refractory CRS and ICANS after CAR T-cell therapy. Blood 2023; 141(20): 2430–2442.

11.

Sheth

Gauthier

Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant 2021; 56(3): 552–566.

12.

Granit

Benatar

Kurtoglu

, et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol 2023; 22(7): 578–590.

13.

Mackensen

Müller

Mougiakakos

, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022; 28(10): 2124–2132.

14.

Müller

Taubmann

Bucci

, et al. CD19 CAR T-cell therapy in autoimmune disease—a case series with follow-up. N Engl J Med 2024; 390(8): 687–700.

15.

Motte

Sgodzai

Schneider-Gold

, et al. Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells. Neuron 2024; 112(11): 1757–1763.e2.

16.

Fischbach

Richter

Pfeffer

, et al. CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis. Med 2024; 5(6): 550–558.e2.

17.

Haghikia

Hegelmaier

Wolleschak

, et al. Anti-CD19 CAR T cells for refractory myasthenia gravis. Lancet Neurol 2023; 22(12): 1104–1105.

18.

Faissner

Motte

Sgodzai

, et al. Successful use of anti-CD19 CAR T cells in severe treatment-refractory stiff-person syndrome. Proc Natl Acad Sci U S A 2024; 121(26): e2403227121.

19.

Wickel

Schnetzke

Sayer-Klink

, et al. Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome. Cell Rep Med 2024; 5(11): 101794.

20.

Qin

Zhang

Mou

, et al. Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity. Sci Immunol 2024; 9(95): eadj9730.

21.

Hegelmaier

Wolleschak

Pappa

, et al. Chimeric antigen receptor T cells in treatment-refractory DAGLA antibody-associated encephalitis. Med 2025; 6(9): 100776.

22.

Cabrera-Maqueda

Sepulveda

García

, et al. CD19-directed CAR T-cells in a patient with refractory MOGAD: clinical and immunologic follow-up for 1 year. Neurol Neuroimmunol Neuroinflamm 2024; 11(5): e200292.

23.

Moersch

Woltman

HW.

Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956; 31(15): 421–427.

24.

Chia

McKeon

Dalakas

, et al. Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria. Ann Clin Transl Neurol 2023; 10(7): 1083–1094.

25.

Dalakas

MC.

Stiff-person syndrome and related disorders—diagnosis, mechanisms and therapies. Nat Rev Neurol 2024; 20(10): 587–601.

26.

Dalakas

Fujii

, et al. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 2000; 55(10): 1531–1535.

27.

Vlad

Wang

Newsome

, et al. Stiff person spectrum disorders—an update and outlook on clinical, pathophysiological and treatment perspectives. Biomedicines 2023; 11(9): 2500.

28.

Budhram

Sechi

Flanagan

, et al. Clinical spectrum of high-titre GAD65 antibodies. J Neurol Neurosurg Psychiatry 2021; 92(6): 645–654.

29.

Thaler

Bangol

Biljecki

, et al. Possible link of genetic variants to autoimmunity in GAD-antibody-associated neurological disorders. J Neurol Sci 2020; 413: 116860.

30.

Graus

Saiz

Dalmau

GAD antibodies in neurological disorders—insights and challenges. Nat Rev Neurol 2020; 16(7): 353–365.

31.

Gresa-Arribas

Ariño

Martínez-Hernández

, et al. Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS One 2015; 10(3): e0121364.

32.

Werner

Haselmann

Weishaupt

, et al. Stiff person-syndrome IgG affects presynaptic GABAergic release mechanisms. J Neural Transm (Vienna) 2015; 122(3): 357–362.

33.

Mitoma

Song

Ishida

, et al. Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci 2000; 175(1): 40–44.

34.

Hansen

Grünewald

Weishaupt

, et al. Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats. Exp Neurol 2013; 239: 202–209.

35.

Stemmler

Rohleder

Malter

, et al. Serum from a patient with GAD65 antibody-associated limbic encephalitis did not alter GABAergic neurotransmission in cultured hippocampal networks. Front Neurol 2015; 6: 189.

36.

Tröscher

Mair

Verdú

Juan

, et al. Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex. Brain 2023; 146(4): 1436–1452.

37.

Carvajal-González

Leite

Waters

, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 2014; 137(Pt 8): 2178–2192.

38.

Carvajal-González

Jacobson

Clover

, et al. Systemic delivery of human GlyR IgG antibody induces GlyR internalization into motor neurons of brainstem and spinal cord with motor dysfunction in mice. Neuropathol Appl Neurobiol 2021; 47(2): 316–327.

39.

Crisp

Dixon

Jacobson

, et al. Glycine receptor autoantibodies disrupt inhibitory neurotransmission. Brain 2019; 142(11): 3398–3410.

40.

Schaefer

Roemer

Janzen

, et al. Impaired glycine receptor trafficking in neurological diseases. Front Mol Neurosci 2018; 11: 291.

41.

Wiessler

Talucci

Piro

, et al. Glycine receptor β-targeting autoantibodies contribute to the pathology of autoimmune diseases. Neurol Neuroimmunol Neuroinflamm 2024; 11(2): e200187.

42.

Wiessler

Zheng

Werner

, et al. Impaired presynaptic function contributes significantly to the pathology of glycine receptor autoantibodies. Neurol Neuroimmunol Neuroinflamm 2025; 12(2): e200364.

43.

Graus

Vogrig

Muñiz-Castrillo

, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm 2021; 8(4): e1014.

44.

Sommer

Weishaupt

Brinkhoff

, et al. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet (London, England) 2005; 365(9468): 1406–1411.

45.

Geis

Weishaupt

Hallermann

, et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010; 133(11): 3166–3180.

46.

Werner

Pauli

Doose

, et al. Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition. Brain 2016; 139(Pt 2): 365–379.

47.

Geis

Grünewald

Weishaupt

, et al. Human IgG directed against amphiphysin induces anxiety behavior in a rat model after intrathecal passive transfer. J Neural Transm (Vienna) 2012; 119(8): 981–985.

48.

Graus

Titulaer

Balu

, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15(4): 391–404.

49.

Abboud

Probasco

Irani

, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry 2021; 92(7): 757–768.

50.

Dalakas

Fujii

, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001; 345(26): 1870–1876.

51.

Dalakas

MC.

Long-term effectiveness of IVIg maintenance therapy in 36 patients with GAD antibody-positive Stiff-Person syndrome. Neurol Neuroimmunol Neuroinflamm 2022; 9(5): e200011.

52.

Dalakas

MC.

Therapies in Stiff-Person syndrome: advances and future prospects based on disease pathophysiology. Neurol Neuroimmunol Neuroinflamm 2023; 10(3): e200109.

53.

Balint

Meinck

HM.

Pragmatic treatment of Stiff Person spectrum disorders. Mov Disord Clin Pract 2018; 5(4): 394–401.

54.

Mercure-Corriveau

Roy

, et al. Therapeutic plasma exchange in the management of stiff person syndrome spectrum disorders: a case series and review of the literature. Ther Adv Neurol Disord 2023; 16: 17562864231180736.

55.

Dalakas

Rakocevic

Dambrosia

, et al. A double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome. Ann Neurol 2017; 82(2): 271–277.

56.

Hao

Davis

Hirsch

, et al. Plasmapheresis and immunosuppression in stiff-man syndrome with type 1 diabetes: a 2-year study. J Neurol 1999; 246(8): 731–735.

57.

Dalakas

MC.

Advances in the pathogenesis and treatment of patients with stiff person syndrome. Curr Neurol Neurosci Rep 2008; 8(1): 48–55.

58.

Husari

Tardo

Greenberg

. Bortezomib for the treatment of refractory Stiff Person spectrum disorder (P2.2-037). Neurology 2019; 92(15_Suppl.): P2.-037.

59.

Sanders

Bredeson

Pringle

, et al. Autologous stem cell transplantation for stiff person syndrome: two cases from the Ottawa blood and marrow transplant program. JAMA Neurol 2014; 71(10): 1296–1299.

60.

Kass-Iliyya

Snowden

Thorpe

, et al. Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience. J Neurol 2021; 268(1): 265–275.

61.

Burt

Balabanov

Han

, et al. Autologous hematopoietic stem cell transplantation for Stiff-Person spectrum disorder: a clinical trial. Neurology 2021; 96(6): e817–e830.

62.

Winklehner

Wickel

Gelpi

, et al. Progressive encephalomyelitis with rigidity and myoclonus with glycine receptor and GAD65 antibodies: case report and potential mechanisms. Neurol Neuroimmunol Neuroinflamm 2024; 11(6): e200298.

63.

Murinson

Guarnaccia

JB.

Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008; 71(24): 1955–1958.

64.

Dubey

Jitprapaikulsan

, et al. Amphiphysin-IgG autoimmune neuropathy: a recognizable clinicopathologic syndrome. Neurology 2019; 93(20): e1873–e1880.

65.

Dalmau

Geis

Graus

Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017; 97(2): 839–887.

66.

Qin

Tian

Zhou

, et al. Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results. Signal Transduct Target Ther 2023; 8(1): 5.

67.

Reincke

von Wardenburg

Homeyer

, et al. Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells. Cell 2023; 186(23): 5084–5097.e18.