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
Copyright © 2023 Elsevier Ltd. All rights reserved..
BACKGROUND: 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.
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.
| Errataetall: |
CommentIn: Lancet Neurol. 2023 Jul;22(7):545-546. - PMID 37353270 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
|---|---|
| Enthalten in: |
The Lancet. Neurology - 22(2023), 7 vom: 23. Juli, Seite 578-590 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Granit, Volkan [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Autoantibodies |
|---|
| Anmerkungen: |
Date Completed 26.06.2023 Date Revised 15.03.2024 published: Print ClinicalTrials.gov: NCT04146051 CommentIn: Lancet Neurol. 2023 Jul;22(7):545-546. - PMID 37353270 Citation Status MEDLINE |
|---|
| doi: |
10.1016/S1474-4422(23)00194-1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM358546508 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM358546508 | ||
| 003 | DE-627 | ||
| 005 | 20240315232649.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/S1474-4422(23)00194-1 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1330.xml |
| 035 | |a (DE-627)NLM358546508 | ||
| 035 | |a (NLM)37353278 | ||
| 035 | |a (PII)S1474-4422(23)00194-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Granit, Volkan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001) |b a prospective, multicentre, open-label, non-randomised phase 1b/2a study |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.06.2023 | ||
| 500 | |a Date Revised 15.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT04146051 | ||
| 500 | |a CommentIn: Lancet Neurol. 2023 Jul;22(7):545-546. - PMID 37353270 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a BACKGROUND: 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 | ||
| 520 | |a METHODS: 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 | ||
| 520 | |a FINDINGS: 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 | ||
| 520 | |a INTERPRETATION: 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 | ||
| 520 | |a FUNDING: Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Autoantibodies |2 NLM | |
| 650 | 7 | |a Receptors, Chimeric Antigen |2 NLM | |
| 700 | 1 | |a Benatar, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Kurtoglu, Metin |e verfasserin |4 aut | |
| 700 | 1 | |a Miljković, Miloš D |e verfasserin |4 aut | |
| 700 | 1 | |a Chahin, Nizar |e verfasserin |4 aut | |
| 700 | 1 | |a Sahagian, Gregory |e verfasserin |4 aut | |
| 700 | 1 | |a Feinberg, Marc H |e verfasserin |4 aut | |
| 700 | 1 | |a Slansky, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Vu, Tuan |e verfasserin |4 aut | |
| 700 | 1 | |a Jewell, Christopher M |e verfasserin |4 aut | |
| 700 | 1 | |a Singer, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a Kalayoglu, Murat V |e verfasserin |4 aut | |
| 700 | 1 | |a Howard, James F |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Mozaffar, Tahseen |e verfasserin |4 aut | |
| 700 | 0 | |a MG-001 Study Team |e verfasserin |4 aut | |
| 700 | 1 | |a Granit, Volkan |e investigator |4 oth | |
| 700 | 1 | |a Benatar, Michael |e investigator |4 oth | |
| 700 | 1 | |a Mozaffar, Tahseen |e investigator |4 oth | |
| 700 | 1 | |a Chahin, Nizar |e investigator |4 oth | |
| 700 | 1 | |a Howard, James F |c Jr |e investigator |4 oth | |
| 700 | 1 | |a Slansky, Adam D |e investigator |4 oth | |
| 700 | 1 | |a Feinberg, Marc H |e investigator |4 oth | |
| 700 | 1 | |a Sahagian, Gregory |e investigator |4 oth | |
| 700 | 1 | |a Vu, Tuan |e investigator |4 oth | |
| 700 | 1 | |a Pereira, Denise |e investigator |4 oth | |
| 700 | 1 | |a Steele, Julie |e investigator |4 oth | |
| 700 | 1 | |a Paredes, Maria Elena |e investigator |4 oth | |
| 700 | 1 | |a Benjamin, Cara |e investigator |4 oth | |
| 700 | 1 | |a Komanduri, Krishna |e investigator |4 oth | |
| 700 | 1 | |a Habib, Ali Aamer |e investigator |4 oth | |
| 700 | 1 | |a Fong, Julia Kimberly |e investigator |4 oth | |
| 700 | 1 | |a De La Cruz, Luis |e investigator |4 oth | |
| 700 | 1 | |a Dimitrova, Diana |e investigator |4 oth | |
| 700 | 1 | |a Chopra, Manisha |e investigator |4 oth | |
| 700 | 1 | |a Holley, Kelly |e investigator |4 oth | |
| 700 | 1 | |a DeMaria, Gabrielle |e investigator |4 oth | |
| 700 | 1 | |a Tenorio, April |e investigator |4 oth | |
| 700 | 1 | |a Requena, Naraly |e investigator |4 oth | |
| 700 | 1 | |a Brooks, Beverly Mackanzie |e investigator |4 oth | |
| 700 | 1 | |a Suresh, Niraja |e investigator |4 oth | |
| 700 | 1 | |a Farias, Jerrica |e investigator |4 oth | |
| 700 | 1 | |a Miljković, Miloš D |e investigator |4 oth | |
| 700 | 1 | |a Kurtoglu, Metin |e investigator |4 oth | |
| 700 | 1 | |a Ngo Casi, Minhtran |e investigator |4 oth | |
| 700 | 1 | |a Chowdhury, Adam |e investigator |4 oth | |
| 700 | 1 | |a Kamboh, Hafsa |e investigator |4 oth | |
| 700 | 1 | |a Stewart, C Andrew |e investigator |4 oth | |
| 700 | 1 | |a Tosun, Mehmet |e investigator |4 oth | |
| 700 | 1 | |a Shang, Yufei |e investigator |4 oth | |
| 700 | 1 | |a Duverney, Matthew T |e investigator |4 oth | |
| 700 | 1 | |a Kireeva, Maria |e investigator |4 oth | |
| 700 | 1 | |a English, Emily |e investigator |4 oth | |
| 700 | 1 | |a Jewell, Christopher |e investigator |4 oth | |
| 700 | 1 | |a Singer, Michael S |e investigator |4 oth | |
| 700 | 1 | |a Kalayoglu, Murat V |e investigator |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t The Lancet. Neurology |d 2002 |g 22(2023), 7 vom: 23. Juli, Seite 578-590 |w (DE-627)NLM126098468 |x 1474-4465 |7 nnns |
| 773 | 1 | 8 | |g volume:22 |g year:2023 |g number:7 |g day:23 |g month:07 |g pages:578-590 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/S1474-4422(23)00194-1 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 22 |j 2023 |e 7 |b 23 |c 07 |h 578-590 | ||