Lambert-Eaton myasthenic syndrome (LEMS), also known as myasthenic syndrome, is a rare, often tumor-associated autoimmune disease involving the presynaptic membrane of the neuromuscular junction that was first described in 1956. Typical clinical symptoms include progressive truncal muscle weakness, ptosis, as well as diplopia, dysarthria, and dysphagia. The disease is caused by pathogenic autoantibodies that target and inhibit the P/Q-type pressure-gated calcium channels (VGCCs) presynaptic to nerve terminals, which is different from the postsynaptic targets of pathogenic autoantibodies that cause myasthenia gravis (MG).
The reversible potassium channel blocker amiperidine can be used to treat myasthenic syndrome symptomatically because it prolongs the action potential and keeps calcium channels open longer, thereby increasing the release of acetylcholine. Some antineoplastic drugs and immunosuppressants or immunomodulators can also treat myasthenic syndrome from the cause. For those patients who do not respond to immunosuppressive therapy, there are also studies trying to achieve therapeutic effects by directly depleting antibody-producing B cells. However, none of these approaches have been proven to be effective in severe cases of myasthenic syndrome, and they further expose patients to the risk of infection from long-term immunosuppressive therapy.
CAR-T cell therapy is a genetic engineering therapy based on T cells. T cells are collected from patients and genetically engineered in the laboratory to express chimeric antigen receptors (CARs). The cells are then expanded and re-infused into the patient as a "living cell drug".
In 2017, the US FDA approved the first CAR-T cell therapy for marketing. Currently, 6 CAR-T cell therapies have been approved by the FDA for the treatment of blood cancers such as B-cell leukemia and lymphoma, and have shown strong therapeutic effects. The most commonly used one is anti-CD19 CAR-T cell therapy, which targets B cells and their malignant progeny through the highly specific and ubiquitous surface antigen CD19 of B cells, thereby treating B cell cancers. In recent years, anti-CD19 CAR-T cell therapy has shown good therapeutic effects on a variety of autoimmune diseases such as systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathy, and myasthenia gravis in clinical studies.
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Researchers from the University Hospital Jena in Germany published a research paper titled "Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome" in Cell Reports Medicine, a subsidiary of Cell. The study used the anti-CD19 CAR-T therapy KYV-101 developed by Kyverna Therapeutics to treat a patient with Lambert-Eaton myasthenic syndrome (LEMS). After 3 months of treatment, the patient's clinical symptoms were significantly improved.
Figure 1. Anti-CD19 CAR-T cell therapy reduced VGCC antibody levels and improved LEMS symptoms. (Wickel J, et al., 2024)
In this latest study, the research team reports a case of idiopathic Lambert-Eaton myasthenic syndrome (LEMS) with high titers of P/Q-type anti-presynaptic VGCC antibodies. For the first time, it was reported that the patient's disease symptoms were significantly improved after treatment with anti-CD19 CAR-T cells.
In this patient, infusion of autologous CAR-T cells resulted in the expansion of CD4+ CAR-T cells with terminally differentiated effector memory cells re-expressing a CD45RA (TEMRA)-like phenotype, indicating cytotoxic killing. ability. After 3 months of infusion, the patient's clinical symptoms improved significantly, such as the patient's walking distance increased eightfold. During the observation period, clinical improvement was associated with a decrease in titers of pathogenic VGCC antibodies and a decrease in antibody-producing B cells.
After treatment, the patient did not experience other treatment-related adverse reactions except for grade 2 cytokine release syndrome and intermittent neutropenia. This suggests that anti-CD19 CAR-T cell therapy is a promising treatment option for patients with Lambert-Eaton myasthenic syndrome (LEMS).
Reference
Wickel J, et al. Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome. Cell Reports Medicine, 2024, 5(11).