RNA CAR T Shows Promise for Myasthenia Gravis

Development of B-cell maturation antigen (BCMA)–directed RNA chimeric antigen receptor T-cell therapy (rCAR T) to treat refractory generalized myasthenia gravis (MG) should continue, write experts in a recent issue of Annals of Clinical & Translational Neurology.¹ Their investigation of patients who received Descartes-08, a BCMA-directed autologous rCAR T, in 6 weekly infusions demonstrated disease severity improvement as soon as 3 months after initial administration, with 72% of the treated patients maintaining their treatment response at 12 months.

“Unlike conventional CAR-T cell therapies that rely on in vivo T-cell expansion to achieve therapeutic concentration, Descartes-08 undergoes ex vivo T-cell proliferation during manufacturing, enabling controlled dosing,” the study authors wrote. “This process allows Descartes-08 to be administered in the outpatient setting and does not require lymphodepleting chemotherapy.”

The treatment dosage of Descartes-08 was 52.5 x 10⁶ cells/kg administered on days 1, 8, 15, 22, 29, and 36.

The phase 1/2a study that provided the data for this analysis took place at community and academic medical centers. Seven patients were included, 5 of whom were female patients. Three of these patients were acetylcholine receptor antibody–positive (AChR Ab+), 2 were muscle-specific tyrosine kinase antibody positive (MuSK Ab+), and 1 was seronegative (had no antibodies for AChR, MuSK, or low-density lipoprotein receptor–related protein 4). For patient outcomes at 2, 3, 6, 9, and 12 months, improvement was evaluated using 4 scales: MG Activities of Daily Living (MG-ADL), MG Composite (MGC), Quantitative MG (QMG), and MG quality of life 15-revised score (QOL-15r).

At baseline, 5 of the 7 patients continued to receive a median dose of 17.5 mg/d of prednisone; this decreased by 5 mg/day by month 12. No patients required intravenous immunoglobulin over the year of follow-up. Between months 3 and 6 after the final infusion, results fluctuated for MG-ADL between 6-point and 8-point improvements in disease severity; for MGC, between 15-point and 20-point improvements; and for QOL-15, between 10-point and 15-point improvements. Steady improvement was seen per QMG, with an 8-point improvement seen at 3 months, which increased to an approximate 12-point improvement. For MG-ADL, MGC, and QMG, a clinically meaningful decrease was at least a 2-point improvement.

In this investigation, there were no overall reports of anaphylaxis or hematologic toxicity, and total immunoglobulin levels did not significantly decrease. | Image Credit: © ArtemisDiana-stock.adobe.com

By month 9, the authors were seeing that all their patients were experiencing ongoing improvement, per mean changes in the following:

• MG-ADL: −6.3 (95% CI, −3.5 to −9.1)
• MGC: −16.6 (95% CI, −13.4 to −19.5)
• QMG: −8.4 (95% CI, −5.2 to −11.6)
• QoL-15r: −12.0 (95% CI, −8.0 to −16.0)

These results were maintained for 5 of the 7 patients at the 12-month follow-up:

• MG-ADL: −4.6 (95% CI, −8.8 to −0.4)
• MGC: −11.3 (95% CI, −18.0 to −4.6)
• QMG −6.3 (95% CI, −10.5 to −2.0)
• QoL-15r: −7.7 (95% CI, −15.6 to −8.4)

Patients could be retreated if they met prespecified criteria, and of the 3 participants who relapsed or did not maintain treatment response, all experienced improvement with retreatment. The retreatment dose was once again 52.5 x 10⁶ cells/kg, administered once weekly for 6 weeks.

Anti-meningococcal antibodies from prior vaccination were seen at baseline in 5 of 7 patients, and following a modest decrease in these at month 3 that deepened by month 9, month 12 brought stabilization. These patients also reported fewer adverse events.

Prior research on Descartes-08 demonstrated similar deep and durable responses,² the present study authors noted, adding strength to their new findings; in particular, that retreatment results were similar to or better than initial treatment. There also were no overall reports of anaphylaxis or hematologic toxicity, and total immunoglobulin levels did not significantly decrease.

“The use of mRNA for autologous CAR T-cell engineering may decrease the risk of several toxicities commonly associated with CAR-Ts engineered with integrating vectors,” the investigators stated. “The favorable safety profile of Descartes-08 contrasts with DNA-based CAR-Ts, which carry oncogenic risk from genomic integration of CAR DNA and require lymphodepletion chemotherapy with potential hematologic toxicities.”

Still, there are limitations on these findings, with the authors noting research needs to continue to answer 3 questions in particular: how durable are responses in the absence of ongoing treatment? Is retreatment achievable in any/all instances of disease worsening? What is the long-term impact of BCMA-directed mRNA CAR T on immunoglobulin levels and vaccine titers?

References

1. Chahin N, Sahagian G, Feinberg MH, et al. Durability of response to B-cell maturation antigen-directed mRNA cell therapy in myasthenia gravis. Ann Clin Transl Neurol. Published online August 26, 2025. doi:10.1002/acn3.70167
2. Granit V, Benatar M, Kurtoglu M, et al; MG-001 study team. 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. Lancet Neurol. 2023;22(7):578-590. doi:10.1016/S1474-4422(23)00194-1