Search

Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III–IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II–IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov , NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were –6 (95% CI –9 to –3) for MG-ADL score, –7 (–11 to –3) for Quantitative Myasthenia Gravis score, –14 (–19 to –9) for Myasthenia Gravis Composite score, and –9 (–15 to –3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health. [ABSTRACT FROM AUTHOR]

• Seismic performance of a moment resisting precast concrete beam-column connection. • Investigated connection method relies on steel components for force transfer. • Connection method offers the potential to provide an acceptable seismic performance. • Behavior of connection is influenced significantly by the steel plate anchorage detail. • Simple detailing modifications improve strength, stiffness and energy dissipation characteristics of connection. Seismic performance of a specific type of moment resisting precast concrete beam-column connection was investigated through reversed cyclic load tests. Structural steel components were incorporated with precast concrete beam and column elements in the experiments to provide a ductile moment resisting connection. Additionally, nonlinear finite element analysis (FEA) of typical monolithic and precast connections was performed to investigate the performance and failure modes of these connections. Concrete Damage Plasticity (CDP) model was used to capture nonlinearities in concrete under cyclic loading. Good agreement was achieved between experimental and numerical results, which indicates that the finite element model is capable of capturing failure modes of the investigated precast connections. Agreement between the experimental and numerical behaviors was valid in terms of both the global load–displacement response as well as the local response, such as the force within connection rods and the beam curvature. Behavior of the precast concrete connection was influenced significantly by the anchorage detail used for steel connection plates and the beam reinforcement detailing in the vicinity of the connection. Simple detailing modifications resulted in major improvements in the performance of connection in terms of strength, stiffness and energy dissipation characteristics. [ABSTRACT FROM AUTHOR]