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

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cellular & molecular immunology 2023-11, Vol.20 (11), p.1300-1312
Hauptverfasser: Chen, Qi, Chia, Adeline, Hang, Shou Kit, Lim, Amy, Koh, Wee Kun, Peng, Yanchun, Gao, Fei, Chen, Jili, Ho, Zack, Wai, Lu-En, Kunasegaran, Kamini, Tan, Anthony Tanoto, Le Bert, Nina, Loh, Chiew Yee, Goh, Yun Shan, Renia, Laurent, Dong, Tao, Vathsala, Anantharaman, Bertoletti, Antonio
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
ISSN:2042-0226
1672-7681
2042-0226
DOI:10.1038/s41423-023-01080-3