BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial

Chimeric antigen receptor (CAR)-T cell therapies have the potential to transform treatment of autoimmune disease by resetting the immune system. However, adoption of cell therapies in the autoimmune space is limited by hurdles such as inpatient administration, lymphodepletion and safety concerns around cytokine release syndrome and non-specific immunosuppression. RNA-based cell therapy has potential to address these limitations. Here we report prespecified exploratory analyses from a successful placebo-controlled, double-blind, randomized phase 2b trial in patients with generalized myasthenia gravis who received Descartes-08, an autologous, RNA-encoded anti-B cell maturation antigen (BCMA) CAR-T cell therapy. In 66.7% of patients (n = 10/15), transient targeting of BCMA with Descartes-08 administered in an outpatient setting without lymphodepletion resulted in durable clinical efficacy. Comparison of Descartes-08-treated (n ≤ 19) and placebo (n ≤ 15) cohorts by flow cytometry, serum profiling, multiplexing cytokine analysis and bulk/single-cell transcriptional analysis reveals a precision retuning of self-reactivity demonstrated by increased pro-immune function, decreased activity of BCMA<sup>+</sup> plasma cells and plasmacytoid dendritic cells and reductions in disease-associated cytokines, such as IL-6. Furthermore, antibody and T cell receptor analysis revealed altered circulating repertoires of self-reactive antibodies and T cell clones among Descartes-08 participants. These effects occurred without immune suppression, indicated by the lack of decline in vaccine-specific antibodies or hypogammaglobulinemia. Our findings unveil a new type of immune reset and support the development of BCMA-targeted RNA cell therapies as a more accessible therapy for autoimmune diseases. ClinicalTrials.gov identifier: NCT04146051 .

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Publication Details

Journal
Nature Medicine
Published
2026-01-09
DOI
https://doi.org/10.1038/s41591-025-04170-z
Citations
2
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
48.39

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article

BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial

Kelsey C. Zorn, Renee Fedak, Tuan Vu, Tara Quesnell et al.
2 citations
Nature Medicine
CAR-T cell therapy research
48.39
article

BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial

Kelsey C. Zorn, Renee Fedak, Tuan Vu, Tara Quesnell, Michael H. Rivner, Emily English, Michael Badruddoja, Chad Pope, Carsten Brunn, Metin Kurtoğlu, Michael S. Singer, Aamir Habib, Elizabeth J. Curvino, Hafsa Kamboh, Thomas Ragole, Amanda Peltier, Charito S. Buensuceso, Matthew T. Duvernay, Miloš D. Miljković, Mithila Vullaganti, Gabrielle DeMaria, Naraly Requena, Heng Xu, S. E. Daniel, Kelly Holley, Murat V. Kalayoglu, Mona Irannejad, Jennifer L. Biaksangi, Yufei Shan, C. Andrew Stewart, Mark S. Anderson, Gregory Sahagian, Juliana F. de Sousa, Chafic Karam, Albina Benson, Adam Slanksy, Joseph L. DeRisi, Rachel N. Ruggerie, George Small, Kelly Gwathmey, Sheetal Shroff, Matthew Karafin, Natalie S. Grover, Manisha Chopra, Catherine Cheng, Rebecca E. Traub, Christopher M. Jewell, Minhtran Ngo-Casi, Bennett Myers, Meg Mendoza, David J. L. Yu, Atanas Filev, Marc H. Feinberg, Jessica Shaw, Darnell Davis, Yara A. Park, Tahseen Mozaffar, Mamatha Pasnoor, Adam English, Aaron Bodansky, James F. Howard, Samantha Rocio Alcántar García, Dina Schneider, Amy Trunnell, Yi Zhang, on behalf the SPPiRE Study Research Team
article en
2 citations

Abstract

Chimeric antigen receptor (CAR)-T cell therapies have the potential to transform treatment of autoimmune disease by resetting the immune system. However, adoption of cell therapies in the autoimmune space is limited by hurdles such as inpatient administration, lymphodepletion and safety concerns around cytokine release syndrome and non-specific immunosuppression. RNA-based cell therapy has potential to address these limitations. Here we report prespecified exploratory analyses from a successful placebo-controlled, double-blind, randomized phase 2b trial in patients with generalized myasthenia gravis who received Descartes-08, an autologous, RNA-encoded anti-B cell maturation antigen (BCMA) CAR-T cell therapy. In 66.7% of patients (n = 10/15), transient targeting of BCMA with Descartes-08 administered in an outpatient setting without lymphodepletion resulted in durable clinical efficacy. Comparison of Descartes-08-treated (n ≤ 19) and placebo (n ≤ 15) cohorts by flow cytometry, serum profiling, multiplexing cytokine analysis and bulk/single-cell transcriptional analysis reveals a precision retuning of self-reactivity demonstrated by increased pro-immune function, decreased activity of BCMA<sup>+</sup> plasma cells and plasmacytoid dendritic cells and reductions in disease-associated cytokines, such as IL-6. Furthermore, antibody and T cell receptor analysis revealed altered circulating repertoires of self-reactive antibodies and T cell clones among Descartes-08 participants. These effects occurred without immune suppression, indicated by the lack of decline in vaccine-specific antibodies or hypogammaglobulinemia. Our findings unveil a new type of immune reset and support the development of BCMA-targeted RNA cell therapies as a more accessible therapy for autoimmune diseases. ClinicalTrials.gov identifier: NCT04146051 .

Nature MedicineVol. 32(3)
University of North Carolina at Chapel Hill (US), Tufts University (US), University Health Network (CA), University of Alberta (CA), University of California, San Francisco (US), Virginia Commonwealth University (US), Vanderbilt University (US), University of California, Irvine (US), Augusta University (US), University of South Florida (US), Allegheny General Hospital (US), Boca Raton Regional Hospital (US), Dent Neurologic Institute (US), Methodist Hospital (US), Chan Zuckerberg Initiative (United States) (US), Center for Neurosciences (US), Neurology Associates (US), University of Kansas Medical Center (US), Neurology Center of Southern California (US), Cara Therapeutics (United States) (US), University of Colorado Anschutz Medical Campus (US), Istanbul University (TR), University of Pennsylvania (US), University of Colorado Denver (US)
Adaptive Biotechnologies, National Institutes of Health
Openalex Percentile: Top 0%
CAR-T cell therapy research
48.39
DOIOpen Access PDFOpenAlex
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