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Engineering immunosuppressive drug-resistant armored (IDRA) SARS-CoV-2 T cells for cell therapy

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Abstract

Solid organ transplant (SOT) recipients receive immunosuppressive drugs (ISDs) and are susceptible to developing severe COVID-19. Here, we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients (n = 136) treated with different ISDs. We demonstrate that a combination of a calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and prednisone (Pred) treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response. Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection. To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients, we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor (TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta, Delta, Gamma, and Omicron variants. This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.

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Data availability

For original data, please contact Antonio Bertoletti (antonio@duke-nus.edu.sg).

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Acknowledgements

We would like to acknowledge the contribution of the Singapore National University Centre for Organ Transplantation team members who helped recruit patients: AV, AL, and WKK. We thank all voluntary blood donors for their donations. We would like to thank the members of AB’s lab for their insights and critique. Finally, we would also like to thank Dr. Yongxu Lu and Prof. Geoffrey L. Smith from the Department of Pathology, University of Cambridge, U.K., for supplying the vaccinia virus-expressing Spike and Nucleocapsid proteins. This study was supported by research funding from the Singapore Ministry of Health’s National Medical Research Council MOH-000019 (MOH-StaR17Nov-001) to Antonio Bertoletti. Part of this work was also supported by the A*ccelerate GAP-funded project (ACCL/19-GAP064-R20H-H) from the Agency of Science, Technology and Research (A*STAR), the Singapore National Medical Research Council COVID-19 Research Fund (COVID19RF-011) and a Start-up University Grant from the Ministry of Education (Singapore) to Laurent Renia. YSG was supported by a Career Development Fund award by A*STAR (SC35/22-805100).

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Authors and Affiliations

  1. Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore

    Qi Chen, Adeline Chia, Shou Kit Hang, Kamini Kunasegaran, Anthony Tanoto Tan, Nina Le Bert & Antonio Bertoletti

  2. National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore

    Amy Lim, Wee Kun Koh & Anantharaman Vathsala

  3. MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Yanchun Peng, Fei Gao, Jili Chen & Tao Dong

  4. Lion TCR Pte Ltd, Singapore, Singapore

    Zack Ho & Lu-En Wai

  5. A*STAR ID labs, Agency for Science, Technology and Research, Singapore, Singapore

    Chiew Yee Loh, Yun Shan Goh & Laurent Renia

  6. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Laurent Renia

  7. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Anantharaman Vathsala

  8. Singapore Immunology Network, A*STAR, Singapore, Singapore

    Antonio Bertoletti

Authors
  1. Qi Chen
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  2. Adeline Chia
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  3. Shou Kit Hang
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  4. Amy Lim
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  8. Jili Chen
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  16. Laurent Renia
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  17. Tao Dong
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  19. Antonio Bertoletti
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Contributions

QC and AB conceptualized and designed the experiments. QC, AC, SKH, KK, YC.P, FG, and JLC performed the experiments. AL, WKK, and AV recruited the transplant patients and collected the samples. ZH and LEW performed the single-cell TCR sequencing experiment. YSG, CYL, and LR generated constructs for EBV-B cells expressing the ancestral and the Omicron variant spike proteins. QC, YCP, ATT, TD, NLB, and AB analyzed and interpreted the data. QC prepared the figures. QC and AB wrote the manuscript. AB designed and coordinated the study and provided funding.

Corresponding author

Correspondence to Antonio Bertoletti.

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Competing interests

AB is a cofounder of and ATT consults for Lion TCR, a biotech company developing T-cell receptors for treatment of virus-related diseases and cancers. ZH and LEW are employees of Lion TCR Pte. Ltd. None of the other authors has any competing interests related to the study.

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Chen, Q., Chia, A., Hang, S.K. et al. Engineering immunosuppressive drug-resistant armored (IDRA) SARS-CoV-2 T cells for cell therapy. Cell Mol Immunol 20, 1300–1312 (2023). https://doi.org/10.1038/s41423-023-01080-3

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