CAR-T cell therapy evaluated in a patient with myasthenia gravis

CAR-T cell therapy evaluated in a patient with myasthenia gravis
CAR-T cell therapy evaluated in a patient with myasthenia gravis

Several treatments insufficiently effective

As the authors report, this woman was diagnosed with anti-AChR-positive generalized myasthenia gravis in 2012. Between November 2021 and May 2023, she developed swallowing and breathing problems, needed walking aids and suffered several myasthenia gravis attacks. Previous treatments, including thymectomy (April 2022), acetylcholinesterase inhibitors (initiated in 2012) and B cell-depleting antibodies (rituximab, administered in April and October 2021) have not stabilized the progression of disease. The patient also received a proteasome inhibitor (bortezomib, administered in May and November 2022), immunosuppressants (mycophenolate mofetil, administered for 21 months), and immunoglobulins (started in October 2021). According to the authors, these treatments have also not been sufficiently effective. More recently, between March and May 2023, the disease progressed despite treatment with glucocorticoids, mycophenolate mofetil and bortezomib.

The authors report that due to the refractory nature of the disease and the success of treatment with anti-CD19 CAR-T cells in autoimmune rheumatic diseases, they decided to treat the patient with this type of cells. Circulating CD19 B lymphocytes, the levels of which, according to the authors, had already been reduced by previous treatments, were eliminated on day 8 (no recovery on day 62). Anti-RAch antibody titers would have decreased by 70% between day 0 and day 62 (from 2,434 nmol/ml to 718 nmol/ml). IgG titers would have remained constant. Consistent with the serological results, muscle strength increased within two months after treatment. The patient was also able to walk without a walker.

No adverse events related to CAR-T cell therapy such as cytokine release syndrome and immune-effector cell-associated neurotoxicity syndrome occurred. However, the woman had developed grade 1) transaminitis that was self-limited and subsided but did not require treatment.

CAR-T cell treatment is one of many current advances

According to Deutsche Gesellschaft für Neurologie (German Neurological Society), the treatment of patients with myasthenia gravis (MG) has seen some progress in recent years. Two phase 3 studies evaluating new drugs, a complement inhibitor and an FcRn receptor inhibitor, have recently been published.

Since 2022, the humanized monoclonal antibody efgartigimod, an inhibitor of the neonatal Fc receptor (FcRn) has been available. This is the first active ingredient available in this class of agents (FcRn modulators). In vivo, FcRn has different functions in the transport and recycling of IgG. Thus, the binding of FcRn to IgG antibodies prevents their degradation. Drug blockade of FcRn prevents IgG from binding to FcRn, allowing the body to eliminate IgG autoantibodies more quickly.

A new FcRn modulator

Rozanolixizumab is a new specific FcRn modulator or inhibitor, whose safety and efficacy in generalized MG (in addition to basic treatment with cholinesterase inhibitors and immunosuppressants) were evaluated in the MycarinG study. In total, 200 affected people (≥ 18 years old) with an MG-ADL score (“ Myasthenia Gravis Activities of Daily Living ) of ≥ 3 as well as a quantitative Myasthenia Gravis score of ≥ 11 were included in the study. Unlike efgartigimod, the study included not only people with anti-AChR antibodies, but also people with anti-MuSK autoantibodies. Participants received subcutaneous infusions of rozanolixizumab once weekly for six weeks, at a dose of 7 mg/kg (n = 66), 10 mg/kg (n = 67), or placebo (n = 67). . The primary endpoint was the reduction in the MG-ADL score until day 43. The improvement was significantly greater in both rozanolixizumab groups than under placebo: under 7 mg/kg, the average change was -3 .37 and under 10 mg/kg -3.4 (versus placebo -0.78; p

Treatment-related serious adverse events (TEAEs) occurred in 8% of patients in the rozanolixizumab 7 mg/kg group, in 10% of patients treated with 10 mg/kg, and in 9% of patients treated with placebo. According to the authors, there were no deaths. The DGN (Deutsche Gesellschaft für Neurologie), therefore indicates that the MycarinG study has therefore confirmed the effectiveness of FcRn inhibition in generalized MG, not only in AChR-positive people but also in people with anti-MuSK autoantibodies ( even if the latter were much less numerous).

A new complement C5 inhibitor

Antibodies inhibiting the complement system constitute the second new group of active ingredients available in terms of therapy. While the monoclonal antibody eculizumab was authorized several years ago for the reduction of therapeutic fracture », ravulizumab, another complement C5 inhibitor, was authorized more widely in 2022 in generalized myasthenia gravis.

Zilucoplan is not a monoclonal antibody but a macrocyclic peptide self-administered once daily subcutaneously. In the RAISE study, zilucoplan was evaluated in 174 affected individuals (aged 18 to 74 years, AChR-AK positive). The participants had a MG-ADL score of ≥ 6 and a quantitative myasthenia gravis score of ≥ 12. They received for 12 weeks subcutaneously once a day (by self-injection) either zilucoplan at a dose of 0.3 mg/kg (n = 86) or a placebo (n = 88). Under zilucoplan, the MG-ADL score decreased by -4.39 versus -2.30 under placebo (significant difference, p = 0.0004). Serious TEAEs and serious infections occurred at approximately the same frequency in both groups. One death was recorded in each group, but both cases were unrelated to the study drug. The causes were Covid-19 infection (in the verum group) and cerebral hemorrhage (in the placebo group).

The two new agents may expand the therapeutic armamentarium for MG in the future, allowing us to treat patients even more individually and more consistently. », comments Professor Heinz Wiendl (Münster). With zilucoplan, we would have a third complement inhibitor for the complementary treatment of generalized MG. The substance is not administered in the form of an IV infusion under medical supervision (every two weeks for eculizumab or every eight weeks for ravulizumab), but injected daily by affected people subcutaneously. “ For many people, for example those who work, this could be more practical on a daily basis “, explained Professor Wiendl.

This article was translated from Univadis.de using several editorial tools, including AI, in the process. The content was reviewed by the editorial staff before publication.

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