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

Cellular & Molecular Immunology volumeĀ 20,Ā pages 1300ā€“1312 (2023)Cite this article

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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 (nā€‰=ā€‰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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For original data, please contact Antonio Bertoletti (antonio@duke-nus.edu.sg).

References

  1. Pan Q, Tilanus HW, Metselaar HJ, Janssen HL, van der Laan LJ. Virus-drug interactions-molecular insight into immunosuppression and HCV. Nat Rev Gastroenterol Hepatol. 2012;9:355ā€“62.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  2. Raja MA, Mendoza MA, Villavicencio A, Anjan S, Reynolds JM, Kittipibul V, et al. COVID-19 in solid organ transplant recipients: A systematic review and meta-analysis of current literature. Transpl Rev. 2021;35:100588.

    ArticleĀ  Google ScholarĀ 

  3. Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant. 2020;20:1800ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  4. Simioli F, Martino M, Annunziata A, Carannante N, Fiorentino G. Therapeutic approach for severe COVID-19 and immunocompromised patients. A case series. Respir Med Case Rep. 2021;33:101397.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  5. Avery RK. Update on COVID-19 therapeutics for solid organ transplant recipients, including the omicron surge. Transplantation. 2022;106:1528ā€“37.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  6. van Laarhoven A, Kurver L, Overheul GJ, Kooistra EJ, Abdo WF, van Crevel R, et al. Interferon gamma immunotherapy in five critically ill COVID-19 patients with impaired cellular immunity: a case series. Medicne. 2021;2:1163ā€“70.e2.

    Google ScholarĀ 

  7. Bertrand D, Hamzaoui M, LemĆ©e V, Lamulle J, Hanoy M, Laurent C, et al. Antibody and T cell response to SARS-CoV-2 messenger RNA BNT162b2 vaccine in kidney transplant recipients and hemodialysis patients. J Am Soc Nephrol. 2021;32:2147ā€“52.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  8. Rincon-Arevalo H, Choi M, Stefanski AL, Halleck F, Weber U, Szelinski F, et al. Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients. Sci Immunol. 2021;6:eabj1031.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  9. Gao Y, Cai C, Wullimann D, Niessl J, Rivera-Ballesteros O, Chen P, et al. Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination. Immunity. 2022;55:1732ā€“46.e5.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  10. Baang JH, Smith C, Mirabelli C, Valesano AL, Manthei DM, Bachman MA, et al. Prolonged severe acute respiratory syndrome coronavirus 2 replication in an immunocompromised patient. J Infect Dis. 2021;223:23ā€“27.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  11. Helleberg M, Niemann CU, Moestrup KS, Kirk O, Lebech AM, Lane C, et al. Persistent COVID-19 in an immunocompromised patient temporarily responsive to two courses of remdesivir therapy. J Infect Dis. 2020;222:1103ā€“7.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  12. Nakajima Y, Ogai A, Furukawa K, Arai R, Anan R, Nakano Y, et al. Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient. J Infect Chemother. 2021;27:387ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  13. Cajanding R. Immunosuppression following organ transplantation. Part 1: mechanisms and immunosuppressive agents. Br J Nurs. 2018;27:920ā€“7.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  14. Casadevall A, Focosi D. SARS-CoV-2 variants resistant to monoclonal antibodies in immunocompromised patients constitute a public health concern. J Clin Investig. 2023;133:e168603.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  15. Tan AT, Linster M, Tan CW, Le Bert N, Chia WN, Kunasegaran K, et al. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. 2021;34:108728.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  16. Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM, et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood. 2010;116:4360ā€“7.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  17. Comoli P, Labirio M, Basso S, Baldanti F, Grossi P, Furione M, et al. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood. 2002;99:2592ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  18. Martits-Chalangari K, Spak CW, Askar M, Killian A, Fisher TL, Atillasoy E, et al. ALVR109, an off-the-shelf partially HLA matched SARS-CoV-2-specific T cell therapy, to treat refractory severe COVID-19 pneumonia in a heart transplant patient: case report. Am J Transplant. 2022;22:1261ā€“5.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  19. Papadopoulou A, Karavalakis G, Papadopoulou E, Xochelli A, Bousiou Z, Vogiatzoglou A, et al. SARS-CoV-2-specific T cell therapy for severe COVID-19: a randomized phase 1/2 trial. Nat Med. 2023;29:2019ā€“29.

  20. Vasileiou S, Hill L, Kuvalekar M, Workineh AG, Watanabe A, Velazquez Y, et al. Allogeneic off-the-shelf SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high-risk patients. Haematologica. 2023;108:1840ā€“50.

  21. Peter L, Wendering DJ, Schlickeiser S, Hoffmann H, Noster R, Wagner DL, et al. Tacrolimus-resistant SARS-CoV-2-specific T cell products to prevent and treat severe COVID-19 in immunosuppressed patients. Mol Ther Methods Clin Dev. 2022;25:52ā€“73.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  22. Hafezi M, Lin M, Chia A, Chua A, Ho ZZ, Fam R, et al. Immunosuppressive drug-resistant armored T-cell receptor T cells for immune therapy of HCC in liver transplant patients. Hepatology. 2021;74:200ā€“13.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  23. De Angelis B, Dotti G, Quintarelli C, Huye LE, Zhang L, Zhang M, et al. Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506). Blood. 2009;114:4784ā€“91.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  24. Yam P, Jensen M, Akkina R, Anderson J, Villacres MC, Wu J, et al. Ex vivo selection and expansion of cells based on expression of a mutated inosine monophosphate dehydrogenase 2 after HIV vector transduction: effects on lymphocytes, monocytes, and CD34+ stem cells. Mol Ther. 2006;14:236ā€“44.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  25. Koh S, Shimasaki N, Suwanarusk R, Ho ZZ, Chia A, Banu N, et al. A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus. Mol Ther Nucleic Acids. 2013;2:e114.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  26. Bertoletti A, Tan AT. Challenges of CAR- and TCR-T cell-based therapy for chronic infections. J Exp Med. 2020;217:e20191663.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  27. Kah J, Koh S, Volz T, Ceccarello E, Allweiss L, LĆ¼tgehetmann M, et al. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. J Clin Investig. 2017;127:3177ā€“88.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  28. Polidoro RB, Hagan RS, de Santis Santiago R, Schmidt NW. Overview: systemic inflammatory response derived from lung injury caused by SARS-CoV-2 infection explains severe outcomes in COVID-19. Front Immunol. 2020;11:1626.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  29. Lim JME, Hang SK, Hariharaputran S, Chia A, Tan N, Lee ES, et al. A comparative characterization of SARS-CoV-2-specific T cells induced by mRNA or inactive virus COVID-19 vaccines. Cell Rep. Med. 2022;3:100793.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  30. Peng Y, Felce SL, Dong D, Penkava F, Mentzer AJ, Yao X, et al. An immunodominant NP105-113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease. Nat Immunol. 2022;23:50ā€“61.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  31. Goh YS, Chavatte JM, Lim Jieling A, Lee B, Hor PX, Amrun SN, et al. Sensitive detection of total anti-Spike antibodies and isotype switching in asymptomatic and symptomatic individuals with COVID-19. Cell Rep. Med. 2021;2:100193.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  32. Goh YS, Rouers A, Fong SW, Zhuo NZ, Hor PX, Loh CY, et al. Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals. Front Immunol. 2022;13:1031852.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  33. Goh YS, Ng LFP, Renia L. A flow cytometry-based assay for serological detection of anti-spike antibodies in COVID-19 patients. STAR Protoc. 2021;2:100671.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  34. Koutsakos M, Reynaldi A, Lee WS, Nguyen J, Amarasena T, Taiaroa G, et al. SARS-CoV-2 breakthrough infection induces rapid memory and de novo T cell response. Immunity. 2023;56:879ā€“892.e4.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  35. Ricciardelli I, Brewin J, Lugthart G, Albon SJ, Pule M, Amrolia PJ. Rapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy. Am J Transplant. 2013;13:3244ā€“52.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  36. Tan AT, Yang N, Lee Krishnamoorthy T, Oei V, Chua A, Zhao X, et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology. 2019;156:1862ā€“76.e9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  37. Qasim W, Brunetto M, Gehring AJ, Xue SA, Schurich A, Khakpoor A, et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol. 2015;62:486ā€“91.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  38. Tometten I, Landmann S, Kantauskaite M, Lamberti J, Hillebrandt J, MĆ¼ller L, et al. Factors associated with vaccine-induced T cell immune responses against SARS-CoV-2 in kidney transplant recipients. J Infect Dis. 2022;227:641ā€“50.

  39. Scurr MJ, Lippiatt G, Capitani L, Bentley K, Lauder SN, Smart K, et al. Magnitude of venous or capillary blood-derived SARS-CoV-2-specific T cell response determines COVID-19 immunity. Nat Commun. 2022;13:5422.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  40. Choi B, Choudhary MC, Regan J, Sparks JA, Padera RF, Qiu X, et al. Persistence and evolution of SARS-CoV-2 in an immunocompromised host. N Engl J Med. 2020;383:2291ā€“3.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  41. Tan AT, Lim JM, Le Bert N, Kunasegaran K, Chia A, Qui MD, et al. Rapid measurement of SARS-CoV-2 spike T cells in whole blood from vaccinated and naturally infected individuals. J Clin Investig. 2021;131:e152379.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  42. Liu J, Yu J, McMahan K, Jacob-Dolan C, He X, Giffin V, et al. CD8 T cells contribute to vaccine protection against SARS-CoV-2 in macaques. Sci Immunol. 2022;7:eabq7647.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  43. Basar R, Uprety N, Ensley E, Daher M, Klein K, Martinez F, et al. Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy. Cell Rep. 2021;36:109432.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  44. Canas CA. The triggering of post-COVID-19 autoimmunity phenomena could be associated with both transient immunosuppression and an inappropriate form of immune reconstitution in susceptible individuals. Med Hypotheses. 2020;145:110345.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  45. Sharma C, Bayry J. High risk of autoimmune diseases after COVID-19. Nat Rev Rheumatol. 2023;19:399ā€“400.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  46. Quach D, Lulla P, Rooney CM. Banking on virus-specific T-cells (VSTS) to fulfill the need for ā€œoff the shelfā€ cell therapies. Blood. 2022;139:799ā€“802.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  47. Bertoletti A, Le Bert N, Tan AT. SARS-CoV-2-specific T cells in the changing landscape of the COVID-19 pandemic. Immunity. 2022;55:1764ā€“78.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

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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 ABā€™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 Healthā€™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,Ā Adeline Chia,Ā Shou Kit Hang,Ā Kamini Kunasegaran,Ā Anthony Tanoto Tan,Ā Nina Le BertĀ &Ā Antonio Bertoletti

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

    Amy Lim,Ā Wee Kun KohĀ &Ā Anantharaman Vathsala

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

    Yanchun Peng,Ā Fei Gao,Ā Jili ChenĀ &Ā Tao Dong

  4. Lion TCR Pte Ltd, Singapore, Singapore

    Zack HoĀ &Ā Lu-En Wai

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

    Chiew Yee Loh,Ā Yun Shan GohĀ &Ā 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

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  1. Qi Chen
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  2. Adeline Chia
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  5. Wee Kun Koh
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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 TCRĀ 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, 1300ā€“1312 (2023). https://doi.org/10.1038/s41423-023-01080-3

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