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Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis

Affiliations
  • 1Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China; National Key Laboratory for Immunity and Inflammation, Shanghai, China.
  • 2Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China; BRL Medicine Inc., Shanghai 201109, China.
  • 3Department of Rheumatology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 4Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
  • 5Department of Radiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
  • 6National Key Laboratory for Immunity and Inflammation, Shanghai, China; Department of Pathology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200082, China.
  • 7Department of Pathology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200082, China.
  • 8Department of Ultrasound, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
  • 9Department of Rheumatology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China.
  • 10Department of Pathology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
  • 11Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 12Department of Rheumatology and Clinical Immunology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang 315040, China.
  • 13School of Medicine, Tsinghua University, Beijing 100084, China.
  • 14Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
  • 15Department of Cardiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
  • 16Department of Dermatology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai Key Laboratory of Medical Mycology, Shanghai 200082, China.
  • 17Department of Rheumatology and Immunology, Shanghai Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 18Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 19Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.
  • 20Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China.
  • 21BRL Medicine Inc., Shanghai 201109, China.
  • 22Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA.
  • 23Department of Rheumatology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: wuhx8855@zju.edu.cn.
  • 24Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China; National Key Laboratory for Immunity and Inflammation, Shanghai, China; School of Medicine, Tsinghua University, Beijing 100084, China; Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: xuhuji@smmu.edu.cn.

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July 16, 2024

Abstract

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

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