Early-Stage Study to Test CD19 CAR T-Cell Therapy YTB323 in Myasthenia Gravis

An ongoing phase 1/2 trial (NCT06704269) is testing the safety, efficacy, and cellular kinetics of YTB323 (Novartis), an investigational, autologous CD19-directed chimeric antigen receptor (CAR) T cell therapy, in patients with generalized myasthenia gravis (gMG). The open-label trial will feature 15 patients to better understand a benefit to risk profile of YTB323 for further development in gMG.¹

The design of this multicenter, non-confirmatory study was presented at the 2025 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 29 to November 1, in San Francisco, California. The study utilizes a single dose design across 2 cohorts, consisting of a sentinel cohort of 3 patients, followed by an expansion cohort of an additional 12 patients. Investigators will use occurrence, severity, and frequency of adverse events (AEs) and serious AEs as the primary outcome measure.

Led by James F. Howard Jr., MD, a professor of neurology, medicine, and allied health in the Department of Neurology at the University of North Carolina at Chapel Hill School of Medicine, the trial includes those aged 18-65 with gMG who are either acetylcholine receptor positive (AChR+) or muscle-specific kinase positive (MuSK). Coming into the study, patients must have treatment-resistant gMG, as defined by Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores of at least 6.

In addition to safety, the study will also look at plasma pharmacokinetics and cellular immunogenicity of YTB323, as well as some preliminary efficacy outcomes like change in MG-ADL score and Quantitative Myasthenia Gravis (QMG) total score. According to clinicaltrials.gov, the phase 1/2 investigation will also record the proportion of patients with a Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS) of minimal manifestations or better and sustained for 6 months post baseline.

In recent years, there has been a growing interest from the neurology community about the potential for CAR-T cell therapy in treating gMG. In this disease, targeting CD19 depletes a broad swath of B-cell lineage, including naïve, memory B cells, and plasmablasts, thereby suppressing autoantibody production more comprehensively than CD20-only approaches. CAR-T cell options are typically a one-time procedure, which some in the field believe may induce prolonged disease control and potentially reduce the amount of immunosuppressants, though durability and benefit need further confirmation.²

READ MORE: Newly Unveiled EPIC Trial Pins Myasthenia Gravis Medications Nipocalimab Against Efgartigimod for Efficacy

Eligible patients for the phase 1/2 trial are required to be on a stable corticosteroid regimen for at least one month before screening and able to taper to at least 10 mg of prednisolone daily (or equivalent) at least one week before leukapheresis; those using cholinesterase inhibitors needed a stable dose for at least two weeks prior.

Patients were excluded if they had purely ocular or mild MG (MGFA I–II), severe bulbar involvement or crisis (MGFA IVb–V), prior transplantation, active or chronic infection (including hepatitis B, hepatitis C, or HIV), uncontrolled inflammatory conditions such as asthma or IBD, known immunodeficiency, or prior exposure to anti-CD19, adoptive T-cell, or other gene therapy products.

Preclinical and clinical data on YTB323, published in Cancer Discovery in 2023, showed that the agent had the same validated CAR as tisagenlecleucel, while enhancing clinical activity at a 25-fold lower dose. Tisagenlecleucel, sold under the brand name Kymriah, was the first CAR-T therapy every approved by the FDA in 2017. It was developed by Novartis and is primarily used in hematologic malignancies, not autoimmune disease.³

Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed promising overall safety (cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)], with overall response rates of 75% and 80% for DL1 and DL2, respectively in adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). In addition, the investigational agent demonstrated comparable CAR T-cell expansion, and preservation of T-cell phenotype, further supporting its development and potential for controlling disease progression in those with DLBCL.

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REFERENCES
1. Howard JF, Meriggioli M, Stengel M, Whittle J. A phase 1/2 study design to assess safety and efficacy of YTB323 in treatment-resistant generalized myasthenia gravis. Presented at: 2025 AANEM Annual Meeting; October 29 to November 1; San Francisco, California. Abstract 157
2. Haghikia A, Hegelmaier T, Wolleschak D, et al. Anti-CD19 CAR T cells for refractory myasthenia gravis. The Lancet Neurol. 2023;22(12):1104-1105. doi:10.1016/S1474-4422(23)00375-7
3. Dickinson MJ, Barba P, Jager U, et al. A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development. Cancer Discov. 2023;13(9):1982-1997. doi:10.1158/2159-8290.CD-22-1276