Molecular Therapy: Methods & Clinical Development (Jun 2022)

Tacrolimus-resistant SARS-CoV-2-specific T cell products to prevent and treat severe COVID-19 in immunosuppressed patients

  • Lena Peter,
  • Désirée Jacqueline Wendering,
  • Stephan Schlickeiser,
  • Henrike Hoffmann,
  • Rebecca Noster,
  • Dimitrios Laurin Wagner,
  • Ghazaleh Zarrinrad,
  • Sandra Münch,
  • Samira Picht,
  • Sarah Schulenberg,
  • Hanieh Moradian,
  • Mir-Farzin Mashreghi,
  • Oliver Klein,
  • Manfred Gossen,
  • Toralf Roch,
  • Nina Babel,
  • Petra Reinke,
  • Hans-Dieter Volk,
  • Leila Amini,
  • Michael Schmueck-Henneresse

Journal volume & issue
Vol. 25
pp. 52 – 73

Abstract

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Solid organ transplant (SOT) recipients receive therapeutic immunosuppression that compromises their immune response to infections and vaccines. For this reason, SOT patients have a high risk of developing severe coronavirus disease 2019 (COVID-19) and an increased risk of death from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Moreover, the efficiency of immunotherapies and vaccines is reduced due to the constant immunosuppression in this patient group. Here, we propose adoptive transfer of SARS-CoV-2-specific T cells made resistant to a common immunosuppressant, tacrolimus, for optimized performance in the immunosuppressed patient. Using a ribonucleoprotein approach of CRISPR-Cas9 technology, we have generated tacrolimus-resistant SARS-CoV-2-specific T cell products from convalescent donors and demonstrate their specificity and function through characterizations at the single-cell level, including flow cytometry, single-cell RNA (scRNA) Cellular Indexing of Transcriptomes and Epitopes (CITE), and T cell receptor (TCR) sequencing analyses. Based on the promising results, we aim for clinical validation of this approach in transplant recipients. Additionally, we propose a combinatory approach with tacrolimus, to prevent an overshooting immune response manifested as bystander T cell activation in the setting of severe COVID-19 immunopathology, and tacrolimus-resistant SARS-CoV-2-specific T cell products, allowing for efficient clearance of viral infection. Our strategy has the potential to prevent severe COVID-19 courses in SOT or autoimmunity settings and to prevent immunopathology while providing viral clearance in severe non-transplant COVID-19 cases.

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