Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study

Abstract

Background: Chimeric antigen receptor (CAR) T-cells are highly effective in treating hematological malignancies, but associated toxicities and necessity of lymphodepletion limit their use in autoimmune disease. To explore the use of CAR T-cells in treating autoimmune disease and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target the B-cell maturation antigen (BCMA) expressed on plasma cells (PC). To test the suitability of our approach, we used rCAR-T to treat patients with myasthenia gravis (MG), a prototypical autoantibody disease mediated in part by pathogenic PCs. Methods: MG-001 was a prospective, multicenter, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T, in adults (age ≥18 years) with generalized MG (gMG) (NCT04146051). Lymphodepletion chemotherapy was not used. In Part-1 (Phase 1b), patients with MGFA Disease Class III–IV gMG would receive three ascending doses of Descartes-08 to determine a Maximum Tolerated Dose (MTD). In Part-2 (Phase 2a), gMG patients with MGFA Disease Class II-IV would receive six doses at the MTD. Part-2 was conducted in the outpatient setting. The primary objective was to establish safety and tolerability; secondary objectives were to assess MG disease severity and biomarkers. Results: 14 participants were enrolled (n=3 in Part-1, n=11 in Part-2). Ten participants were women and four were men. Median follow-up in Part-2 was 5 months (range: 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome (CRS), or neurotoxicity. Common adverse events were headache, nausea/vomiting, and fever, which resolved within 24 hours of infusion. Fevers were not associated with elevated markers of CRS (interleukin-6, interleukin-2, and tumor necrosis factor-α). Mean [95% confidence interval] improvements from baseline to Week 12 were −5·9 [−9, −2·8] for MG-ADL, −7 [−11, −3] for QMG, −14 [−19, −9] for MGC, and −9 [−15, −3] for MG-QoL-15r. Conclusion: In this first study of an rCAR-T therapy in an autoimmune disease, Descartes-08 appeared safe and was well-tolerated. Descartes-08 infusions were followed by numerical decreases on MG severity scales equal to or above what is considered clinically meaningful and persisting on most recent follow-up of up to 9 months. rCAR-T therapy warrants further investigation as a potential new modality to treat autoimmune disease. Funding: Cartesian Therapeutics. Research reported in this publication was also supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Awards Number R25NS088248 and NS115426-01A1.