In-Vivo CAR-T Therapy for Autoimmune Neuropathy: Mechanisms, Clinical Applications, and Emerging Evidence

Abstract

Autoimmune neuropathies encompass a spectrum of immune-mediated disorders affecting the peripheral nervous system, resulting in significant morbidity and functional impairment. The rapid evolution of immunotherapeutic strategies, particularly chimeric antigen receptor T-cell (CAR-T) therapy, has shifted paradigms in the management of refractory autoimmune conditions. In-vivo CAR-T approaches, wherein T-cells are genetically modified within the patient\"s body, offer new avenues for targeted immunomodulation. This review synthesizes current evidence on in-vivo CAR-T therapy for autoimmune neuropathies, elucidates underlying mechanisms, and discusses clinical outcomes, practical considerations, and future directions relevant to healthcare professionals.

Introduction

Autoimmune neuropathy refers to a group of disorders characterized by immune-mediated injury of peripheral nerves, with classic examples including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti-MAG neuropathy. Conventional therapies—such as corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis—frequently provide only partial or transient benefit, and a subset of patients exhibits treatment resistance or relapsing disease. The emergence of cellular immunotherapy, especially CAR-T cell strategies, has revolutionized oncology and is now being explored for autoimmune indications. In-vivo CAR-T involves delivering gene-editing constructs directly into patients to reprogram their endogenous T-cells for targeted immune intervention, potentially overcoming limitations of ex-vivo manufacturing and expanding access. This article reviews the clinical rationale, mechanistic basis, and evolving clinical landscape of in-vivo CAR-T therapy for autoimmune neuropathy.

Epidemiology / Disease Burden

Autoimmune neuropathies collectively affect an estimated 1-8 per 100,000 individuals, with CIDP representing the most prevalent subtype. Disease burden is substantial, encompassing chronic disability, reduced quality of life, and high healthcare utilization. Refractory cases contribute disproportionately to morbidity and healthcare costs, underlining the unmet need for more efficacious and durable treatments. Epidemiologic studies also indicate variable prevalence based on geographic, genetic, and environmental factors, further complicating disease management and resource allocation.

Pathophysiology

The pathogenesis of autoimmune neuropathies involves aberrant activation of autoreactive T-cells and B-cells, breakdown of peripheral nerve tolerance, and subsequent immune-mediated demyelination or axonal injury. Antibodies targeting gangliosides or myelin-associated glycoprotein (MAG) and the infiltration of activated lymphocytes into peripheral nerves orchestrate a cascade of complement activation, macrophage recruitment, and direct cytotoxicity. In-vivo CAR-T therapies are designed to selectively deplete pathogenic immune cell subsets—such as autoreactive B-cells or plasma cells—by engineering T-cells to express synthetic receptors that recognize disease-specific antigens.

Risk Factors

Genetic susceptibility, preceding infections (notably Campylobacter jejuni and Epstein-Barr virus), environmental exposures, and comorbid autoimmune conditions are established risk factors for autoimmune neuropathies. HLA-DRB1 alleles and other immune regulatory gene polymorphisms have been associated with increased risk. In the context of CAR-T therapy, patient selection must consider immune status, infection risk, and comorbidities that may affect therapeutic efficacy or safety.

Clinical Features

Autoimmune neuropathies typically present with progressive, symmetric limb weakness, sensory disturbances, diminished reflexes, and, in some subtypes, cranial nerve involvement. Disease course varies from acute to chronic relapsing forms. Severe cases may exhibit respiratory compromise or significant functional dependency. Refractory disease is characterized by poor response or relapse after first-line immunotherapy, highlighting the need for innovative treatment modalities such as CAR-T.

Diagnosis

Diagnosis is based on a combination of clinical assessment, electrodiagnostic studies (nerve conduction velocity, electromyography), cerebrospinal fluid analysis (albuminocytological dissociation), and exclusion of alternative etiologies. Autoantibody testing (e.g., anti-GM1, anti-MAG) and nerve biopsy may provide supportive evidence in challenging cases. Stratifying patients for in-vivo CAR-T therapy requires careful evaluation of disease activity, prior treatment history, and comorbid conditions.

Treatment & Management

Current first-line treatments include corticosteroids, IVIg, and plasma exchange, aiming to suppress immune activation and ameliorate symptoms. Second-line and adjunctive therapies comprise immunosuppressant agents (azathioprine, cyclosporine, rituximab) for patients with refractory or relapsing disease. The limitations of existing treatments—partial responses, adverse effects, and relapse—drive interest in more targeted immunotherapeutic options. In-vivo CAR-T therapy offers the potential for selective and sustained depletion of autoreactive immune cell populations, with the goal of inducing durable remission.

Recent Advances / Emerging Therapies

CAR-T cell therapy has demonstrated transformative efficacy in hematologic malignancies, and its application in autoimmunity is rapidly advancing. In-vivo CAR-T platforms utilize viral vectors or non-viral delivery systems (e.g., lipid nanoparticles) to introduce CAR constructs into T-cells within the patient\"s body, bypassing the complexities of ex-vivo cell manufacturing. Early preclinical models have shown successful depletion of autoreactive B-cells and reversal of disease phenotypes in murine models of autoimmune neuropathy. Ongoing clinical trials are evaluating safety, feasibility, and preliminary efficacy in human subjects, with encouraging signals regarding disease stabilization and reduction in pathogenic antibody titers. Innovations such as transient CAR expression, suicide switches, and antigen specificity refinements aim to enhance safety and minimize off-target effects.

Guideline Recommendations

While conventional immunotherapies remain the standard of care, international neurology and immunology societies acknowledge the need for novel interventions in refractory cases. Expert consensus supports enrollment of eligible patients in clinical trials evaluating in-vivo CAR-T approaches, with ongoing surveillance for adverse events such as cytokine release syndrome (CRS), neurotoxicity, and immunosuppression. Multidisciplinary management, including neurology, immunology, and infectious disease expertise, is recommended for patient selection and peri-procedural care.

Conclusion

In-vivo CAR-T therapy represents a promising frontier in the management of autoimmune neuropathies, offering the potential for targeted, durable immunomodulation in patients with refractory disease. Ongoing research will clarify optimal protocols, safety profiles, and long-term outcomes. As evidence matures, in-vivo CAR-T may become an integral component of precision immunotherapy for complex autoimmune neurological disorders, expanding therapeutic horizons for clinicians and patients alike.