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The first study to use an RNA-based chimeric antigen receptor T-cell (rCAR-T) therapy in autoimmune disease showed people with generalized myasthenia gravis tolerated the treatment well and experienced improvements in disease severity scales.

In the phase Ib/II , no study-related serious adverse events or cases of dose-limiting toxicity, cytokine release syndrome, or neurotoxicity emerged in any of 14 participants, reported James Howard Jr., MD, of the University of North Carolina in Chapel Hill, and co-authors.

Although four participants developed fevers, all resolved within 24 hours of infusion and were not associated with cytokine release syndrome, the researchers wrote in .

Mean improvements from baseline to week 12 were seen on four validated scales, including:

• 6 points on Myasthenia Gravis-Activities of Daily Living (MG-ADL) score
• 7 points on Quantitative Myasthenia Gravis (QMG) score
• 14 points on Myasthenia Gravis Composite (MGC) score
• 9 points on Myasthenia Gravis Quality of Life 15-revised (MG-QoL-15r) score

A 2-point change on the MG-ADL and a 3-point change in QMG and MGC are considered clinically meaningful, Howard and colleagues noted. No consensus exists as to what is considered a clinically meaningful change in the MG-QoL-15r, they added.

MG-001 was an open label, phase Ib/IIa trial that studied the autologous anti-B-cell maturation antigen (BCMA) rCAR-T therapy Descartes-08 in adults with generalized myasthenia gravis.

In the phase Ib dose-finding portion of the study, three patients with (MGFA) class III-IV disease received three increasing doses of Descartes-08 to determine a maximum tolerated dose. During phase IIa, 11 patients with MGFA class II-IV disease received six doses at the maximum tolerated dose in an outpatient setting.

DNA-based CAR-T therapies, which become a permanent part of the T-cell genome and replicate with each cell division, are used successfully to treat various advanced hematological cancers. But their often-severe toxicities and pre-treatment requirements for lymphodepleting chemotherapy have limited their use to the oncology setting.

Within autoimmune disease indications, patients with severe forms of systemic lupus erythematosus and neuromyelitis optica have received DNA-based CAR T-cell therapies, the authors noted. Their use has been limited to clinical studies and has required extensive inpatient-based monitoring.

In MG-001, the investigators engineered the cells with RNA, rather than DNA, "on the premise that the temporary, non-replicable influence of mRNA would confer predictable pharmacokinetics and consequently a more favorable safety profile," Howard and co-authors wrote, noting that these advances in RNA engineering were the same that enabled the widespread use of mRNA in vaccines.

"The elegant RNA-based approach to CAR T cells used by these investigators has the advantage over standard DNA-based CAR T-cell therapy, that potentially harmful lymphodepletion chemotherapy is not required for rCAR-T engineering," wrote Andreas Meisel, MD, of Charité Universitaetsmedizin Berlin, in an .

"A major finding is the feasibility of producing rCAR-T from patients with generalized myasthenia gravis treated by standard immunosuppressive therapies," he added.

Each study patient had previously received at least one dose of intravenous immunoglobulin, corticosteroids, non-steroidal immune suppressants, or plasma exchange. Despite the use of immunosuppressants, the investigators were able to produce Descartes-08 cells from all participants, with a potency similar to that from a healthy volunteer.

Howard and co-authors recorded that CAR RNA was detected in participants' peripheral blood only at 1 to 2 hours after infusion, noting that this finding supported the feasibility of using rCAR-T therapies in the outpatient setting.

"Although DNA-based CAR T-cell therapies are also moving to the outpatient setting, they still require close monitoring after infusion, with daily clinic visits and reservation of hospital beds in case severe toxicities develop," they wrote. "In accordance with time-restricted expression of RNA-based CAR molecules in vitro, mRNA detection in our study was transient."

The MG-001 trial has broader implications, suggested Meisel: "Myasthenia gravis can serve as a model disease for exploring this innovative therapeutic approach, which is also of great interest for other autoantibody-mediated neurological diseases, such as autoimmune encephalitis."

The study had several limitations, the authors acknowledged, including its small size and the fact that it was unblinded. An ongoing phase IIb part of the MG-001 trial has a targeted enrollment of 30 patients and includes a placebo group.

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