Modern Immune and Cellular Therapies in Neurology: CAR-T and New Directions

Cellular immune technologies are rapidly evolving, opening up new possibilities for the treatment of neuroimmunological diseases. In addition to classical monoclonal antibodies, CAR-T cell therapy is coming to the forefront — a method capable of profoundly reshaping the immune system by selectively eliminating pathogenic B cells and plasma cells.

Particular interest is focused on antibody-mediated diseases of the central and peripheral nervous system: multiple sclerosis, NMOSD (neuromyelitis optica spectrum disorders), MOGAD, autoimmune encephalitides, chronic demyelinating neuropathies and myasthenia gravis. In these conditions, cellular technologies may become an alternative to long-term maintenance immunosuppression.

How CAR-T Works: Basic Mechanisms of Action

CAR-T (Chimeric Antigen Receptor T-cells) are genetically modified T lymphocytes of the patient in which, using viral or non-viral vectors, a chimeric antigen receptor (CAR) is introduced. This receptor recognizes a specific antigen (most often CD19 on B cells) and, upon contact with it, triggers T-cell activation, proliferation and cytotoxic response.

Elimination of Pathogenic B Cells and Plasma Cells

After infusion, CAR-T cells circulate in the body and:

• recognize CD19+ B cells (naïve, memory B cells and part of plasma cells);
• eliminate clones responsible for the production of autoantibodies;
• target long-lived B-cell reservoirs in lymphoid organs.

The principal difference from anti-CD20 drugs (rituximab, ocrelizumab) is that CAR-T also acts on cell populations that are only partially accessible to classical B-cell depletion, and may affect some plasma cells as well.

Immune “Reboot”

After profound depletion of pathogenic B cells and plasma cells:

• levels of autoantibodies (AQP4-IgG, MOG-IgG, AChR-IgG and others) decrease;
• Th17 responses are reduced;
• the relative proportion of regulatory T cells increases;
• immune balance between effector responses and tolerance is restored.

This effect resembles autologous hematopoietic stem cell transplantation (AHSCT), but is achieved in a more targeted way and, potentially, with lower toxicity.

Long-Term Immune Memory

CAR-T cells may persist in the body for months or even years, maintaining long-term remission through surveillance of newly emerging pathogenic B cells. This may explain the possibility of durable benefit after a single procedure.

Results of Cellular Technologies in Different Neuroimmunological Diseases

Multiple Sclerosis (MS)

For MS, there are still no large clinical trials of CAR-T, but several important sources of data exist:

• Preclinical models (EAE): CAR-T cells against B-cell targets suppress inflammation, reduce infiltration of CD4+ T cells and macrophages, and decrease demyelination.
• Observations in patients with hematologic malignancies and coexisting MS: after CAR-T therapy given for hematologic indications, active lesions disappeared on MRI and clinical MS activity decreased.

From a pathogenesis perspective, CAR-T may impact a key link in MS — memory B cells and plasma cells that maintain chronic autoimmune inflammation. In the future, CAR-T is being considered as a potential “one-time therapy” for severe, treatment-refractory MS, comparable in depth of effect to AHSCT but potentially less toxic.

NMOSD (Neuromyelitis Optica Spectrum Disorder)

NMOSD is a classic example of an antibody-mediated disease (AQP4-IgG). Plasma cells producing AQP4 antibodies may persist for decades and are not always eliminated by rituximab or satralizumab.

In preclinical models and isolated clinical observations, CAR-T therapy has led to:

• decrease in AQP4-IgG titers up to seronegativity;
• reduction or complete cessation of relapses;
• stabilization or improvement of neurological status.

NMOSD is one of the most pathogenetically well-justified indications for CAR-T, especially in severe variants resistant to standard therapies.

MOGAD (MOG Antibody-Associated Disease)

MOGAD is often characterized by steroid-dependent or steroid-resistant disease courses, and anti-CD20 therapy may be less effective than in NMOSD.

By targeting key B-cell populations, CAR-T theoretically can:

• reduce MOG-IgG titers;
• decrease relapse rates and steroid requirements;
• provide long-term remission.

Data are still limited to experimental models and single case reports, but the pathogenetic rationale for CAR-T in MOGAD is very strong.

Autoimmune Encephalitides

CAR-T has already been used in severe, treatment-refractory autoimmune encephalitides (anti-NMDA-R, anti-GAD65, DAGLA and others) where conventional regimens (steroids, IVIG, plasmapheresis, rituximab) failed to induce remission.

The main effects observed in these reports include:

• rapid recovery of consciousness and behavior;
• improvement in cognitive functions;
• normalization or marked improvement on EEG and MRI;
• reduction or disappearance of autoantibodies;
• absence of relapses during follow-up.

Autoimmune encephalitides are among the most promising targets for CAR-T, since the pathogenic role of autoantibodies is especially evident.

Chronic Autoimmune Neuropathies

CAR-T therapy has been used in patients with severe, refractory forms of:

• CIDP (chronic inflammatory demyelinating polyneuropathy);
• anti-NF155- and anti-CNTN1-associated neuropathies (often IgG4-mediated).

Reported outcomes include:

• reduction in weakness and improvement in gait;
• reduced need for or discontinuation of regular IVIG and plasmapheresis;
• improvement of electrophysiological parameters (conduction velocities and amplitudes).

CAR-T is particularly attractive for IgG4-mediated neuropathies, where the role of plasma cells is especially prominent.

Myasthenia Gravis

Myasthenia gravis is currently the best-studied neurological disease with regard to CAR-T therapy.

In clinical trials of CD19- and BCMA/CD19-directed CAR-T cells in patients with severe generalized myasthenia gravis, the following effects were observed:

• marked reduction in AChR-IgG and other pathogenic antibodies;
• improvement in MG-ADL, QMG and overall functional status;
• possibility to discontinue IVIG or significantly reduce its dose;
• durable remission for months after a single infusion;
• absence of severe ICANS, with manageable CRS.

Data on dual BCMA/CD19 CAR-T are particularly interesting, since this approach simultaneously targets B cells and plasma cells and may provide even deeper remission.

Advantages of CAR-T Compared to Other Immune Therapies

Adverse Events: CRS, ICANS and Atypical PML Risk

Cytokine Release Syndrome (CRS)

CRS is the most common complication of CAR-T therapy, both in oncology and neuroimmunology. It usually develops within the first 1–4 days after infusion.

Main manifestations: fever, chills, tachycardia, hypotension, elevated CRP and ferritin; in severe cases, multi-organ failure.

Treatment includes tocilizumab, and if necessary, glucocorticoids and intensive monitoring. In neurological patients, CRS often has a milder course, but requires readiness for prompt intervention.

ICANS — Immune Cell-Associated Neurotoxicity Syndrome

ICANS typically appears on days 3–7 after infusion.

Possible symptoms:

• dysarthria or aphasia;
• confusion, disorientation;
• headache, tremor;
• seizures;
• in rare cases, cerebral edema.

In most cases, ICANS is reversible with timely administration of steroids and supportive care. In patients with pre-existing neurological deficits, evaluation by a neurologist is essential, as ICANS may mimic or exacerbate underlying impairment.

Atypical Progressive Multifocal Leukoencephalopathy (PML)

Classical PML is more often associated with natalizumab and anti-CD20 therapies, but prolonged and profound B-cell depletion after CAR-T may theoretically increase the risk of atypical JC-virus reactivation, especially in the presence of significant hypogammaglobulinemia.

• the clinical picture may be less typical, with predominance of cognitive and behavioral changes;
• risk increases when IgG levels are low;
• regular monitoring of immunoglobulin levels, JC virus and planned MRI is recommended.

This complication remains rare, but is important for long-term follow-up of patients receiving cellular therapy.

Future Directions for Cellular Immune Technologies

• development of CAR-Treg — regulatory T cells capable not only of eliminating pathogenic cells but also of restoring immune tolerance;
• creation of universal allogeneic “off-the-shelf” CAR-T products not requiring autologous cell collection;
• personalized cellular approaches for rare antibody-mediated diseases;
• large randomized trials in MS, NMOSD, MOGAD, autoimmune encephalitides and myasthenia gravis;
• combined strategies, including stepwise “CAR-T induction → maintenance targeted therapy”.

References

1. Chinas NA, Alexopoulos H. CAR T-cells meet autoimmune neurological diseases: a new dawn for therapy. Front Immunol. 2025;16:1604174.
   DOI: 10.3389/fimmu.2025.1604174
2. Brittain G, et al. The role of chimeric antigen receptor T-cell therapy in immune-mediated neurological diseases. Ann Neurol. 2024;96(3):441–452.
   DOI: 10.1002/ana.27029
3. Hegelmaier T, et al. Chimeric antigen receptor T cells in treatment-refractory DAGLA antibody-associated encephalitis. Med (N Y). 2025;6(9):100776.
   DOI: 10.1016/j.medj.2025.100776
4. Granit V, Benatar M, Kurtoglu M, et al. Autologous RNA CAR-T in myasthenia gravis (MG-001): phase 1b/2a study. Lancet Neurol. 2023;22(7):578–590.
   DOI: 10.1016/S1474-4422(23)00194-1
5. Li YR, Li J, Yang L. Frontiers in CAR-T cell therapy for autoimmune diseases. Trends Pharmacol Sci. 2024;45(9):839–857.
   DOI: 10.1016/j.tips.2024.07.005
6. Zhang Y, Liu D, Zhang Z, et al. Anti-BCMA/CD19 CAR T-cell therapy in refractory generalized myasthenia gravis: phase 1 trial. EClinicalMedicine. 2025;90:103621.
   DOI: 10.1016/j.eclinm.2025.103621