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Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus

Nature Medicine volume 28, pages 2124–2132 (2022)Cite this article

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An Author Correction to this article was published on 03 November 2022

Abstract

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1 × 106 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment. Reappearing B cells were naïve and showed non-class-switched B cell receptors. CAR T cell treatment was well tolerated with only mild cytokine-release syndrome. These data suggest that CD19 CAR T cell transfer is feasible, tolerable and highly effective in SLE.

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Fig. 1: Description of process and CAR T cell generation.
Fig. 2: CAR T cell expansion in vivo and depletion of B cells.
Fig. 3: Effects of CAR T cell treatment on the activity of systemic lupus erythematosus.
Fig. 4: Long-term follow-up and analysis of recurrent B cells.
Fig. 5: Safety of CAR T cell treatment in systemic lupus erythematosus.

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Data availability

All numeric data from this paper can be obtained at https://mega.nz/file/EXUFmIrT#dIj24lI99kfqQLr52_vz_-2mhJFQKncz9Dumz3qETfk. Patient data can only be shared in pseudonymized form. Otherwise, there are no restrictions to data access. All data graphs in the figures (Figs. 1b–h, 2d, 3a–f, 4a–d and 5a–f) show raw data and depict individual values. Source data are provided with this paper.

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Acknowledgements

The study was supported by the Deutsche Forschungsgemeinschaft (FOR2886, CRC1181 and TRR221), the Bundesministerium für Bildung und Forschung (BMBF; MASCARA), the European Union (ERC Synergy grant 4D Nanoscope, ERC Consolidator grant INSPIRE) and the IMI-funded project RTCure. We thank S. Miltenyi for fruitful discussions and S. Winkler for technical assistance.

Author information

Author notes

  1. These authors contributed equally: Andreas Mackensen, Fabian Müller, Dimitrios Mougiakakos, Gerhard Krönke, Georg Schett.

Authors and Affiliations

  1. Department of Internal Medicine 5—Hematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany

    Andreas Mackensen, Fabian Müller, Dimitrios Mougiakakos, Michael Aigner, Simon Völkl, Sascha Kretschmann, Soraya Kharboutli, Regina Gary, Hannah Reimann & Wolf Rösler

  2. Deutsches Zentrum für Immuntherapie (DZI), Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Andreas Mackensen, Fabian Müller, Dimitrios Mougiakakos, Sebastian Böltz, Artur Wilhelm, Michael Aigner, Simon Völkl, David Simon, Arnd Kleyer, Luis Munoz, Sascha Kretschmann, Soraya Kharboutli, Regina Gary, Hannah Reimann, Wolf Rösler, Stefan Uderhardt, Martin Herrmann, Gerhard Krönke & Georg Schett

  3. Department of Hematology and Oncology, Otto-von-Guericke University Magdeburg (OVGU), Magdeburg, Germany

    Dimitrios Mougiakakos

  4. Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Sebastian Böltz, Artur Wilhelm, David Simon, Arnd Kleyer, Luis Munoz, Stefan Uderhardt, Martin Herrmann, Gerhard Krönke & Georg Schett

  5. Orgentec, Mainz, Germany

    Holger Bang

  6. Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Arif Bülent Ekici & Christian Buettner

  7. Division of Genetics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany

    Katharina Marie Habenicht & Thomas H. Winkler

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  1. Andreas Mackensen
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Contributions

A.M., D.M., G.K. and G.S. designed the treatments and analyses. F.M., S.B. and W.R. monitored the patients. D.S., A.K., S. Kretschmann and S.U. collected clinical data. A.M., L.M., H.R., H.B., M.H., A.B.E., C.B., K.M.H. and T.W. performed molecular analyses. M.A., S. Kharboutli and R.G. produced CAR T cells. S.V. performed immune monitoring. G.S. and A.M. wrote the manuscript.

Corresponding author

Correspondence to Georg Schett.

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Competing interests

There are no competing interests related to this study. The study received no commercial funding. F.M., S.B., A.W., M.A., S.V., D.S., A.K., L.M., S. Kretschmann, S. Kharboutli, R.G., H.R., W.R., S.U., M.H., A.B.E., C.B., K.M.H. and T.W. declare no competing interests. A.M. received speaker honoraria from BMS, Celgene, Gilead, Janssen, KITE, Miltenyi Biomedicine and Novartis, which were not related to this study. G.K. has received speaker honoraria from AbbVie, BMS, Eli Lilly, GSK, Janssen, Novartis and Sanofi. D.M. received speaker honoraria from AbbVie, Amgen, AstraZeneca, BMS, Celgene, Gilead, Hexal, Jazz Pharmaceuticals, Miltenyi Biomedicine, Novartis, Roche and Takeda, which were not related to this study. H.B. is employee of Orgentec and provided quantitative analyses for autoantibodies against nuclear antigens free of charge. G.S. received speaker honoraria from AbbVie, Janssen and Novartis, which were not related to this study.

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Nature Medicine thanks Jessica Manson, Jane Salmon and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer review information: Primary Handling editor: Jennifer Sargent, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1

Consort Flow Diagram. Flow diagram showing eligibility criteria for patients with systemic lupus erythematosus (SLE) to receive treatment with CD19 chimeric antigen receptor (CAR) T cells. Of the 14 SLE patients screened, 2 had no active involvement of the inner organs, 4 had not received all treatments approved for SLE and 1 patient did not understand the procedure. The remaining 7 SLE patients were reviewed by an interdisciplinary specialist board, refusing treatment in 1 patient with concomitant psoriatic disease. One more patient did not consent leaving 5 SLE patients starting CAR T cell therapy. Safety, short time efficacy and long term efficacy endpoints are also shown.

Extended Data Fig. 2 CAR T cell differentiation in vivo.

Immunophenotyping of T cells expressing the chimeric antigen receptor (CAR) (A) and those not expressing the CAR (non-CAR, B). Peripheral blood mononuclear cells from the 5 Systemic Lupus Erythematosus (SLE) patients that received CAR T cells were analyzed using FACS analysis. T cells were analyzed 3, 9, 16, 23, 30 and 60 days after CAR T cell treatment. Stainings distinguished naïve T cells (CD45RA + CD27+), central memory cells (CD45RA-CD27+), effector memory T cells (CD27-CD45RA-) and effector memory T cells re-expressing CD45RA (TEMRA). Each bar represents data from one patient at one specific time point; left to right shows SLE patient 1 to 5. NA, not analyzed.

Source data

Extended Data Fig. 3 Interferon-alpha levels.

Serum levels of interferon (IFN)-alpha at baseline and 3 months after treatment with chimeric antigen receptor (CAR) T cells. IFN-alpha was measured by enzyme-linked immunosorbent assay and detectable in 3 out of 5 patients at baseline and in none of the patients 3 months after CAR T cell therapy.

Source data

Extended Data Fig. 4 Antibody levels against infection agents and vaccinations.

Antibody levels against measles, rubella, mumps, varicella zoster virus (VZV), hepatitis B (HBs, hepatitis B surface antigen), tetanus, diphtheria and pneumococci (PPV23, polyvalent pneumococcal vaccine -23) at baseline and 3 months after CAR T cell administration (N = 5).

Source data

Extended Data Fig. 5 Gating strategy for CAR detection.

Relevant for data presented in Figs. 1 and 2; Time parameter was used to monitor instrument stability, doublets were excluded by FSC-H/FSC-A, CD45+ events were gated, lymphocytes were determined by FSC-A/SSC-A, viable T cells were gated by CD3+ and 7-AAD−, and further subdivided in CAR+ and CAR− T cells. CAR+ and CAR− T cells were analyzed for PD1, CD57, CD27, and CD45RA expression.

Supplementary information

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Mackensen, A., Müller, F., Mougiakakos, D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132 (2022). https://doi.org/10.1038/s41591-022-02017-5

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