Papadopoulou, A., Karavalakis, G., Papadopoulou, E., Xochelli, A., Bousiou, Z., Vogiatzoglou, A., Papayanni, PG., Georgakopoulou, A., Giannaki, M., Stavridou, F., Vallianou, I., Kammenou, M., Varsamoudi, E., Papadimitriou, V., Giannaki, C., Sileli, M., Stergiouda, Z., Stefanou, G., Kourlaba, G., Gounelas, G., Triantafyllidou, M., Siotou, E., Karaglani, A., Zotou, E., Chatzika, G., Boukla, A., Papalexandri, A., Koutra, MG., Apostolou, D., Pitsiou, G., Morfesis, P., Doumas, M., Κarampatakis, T., Kapravelos, N., Bitzani, M., Theodorakopoulou M, Serasli E., Georgolopoulos, G., Sakellari, I., Fylaktou, A., Tryfon, S., Anagnostopoulos, A., Yannaki, E. INat Med. 2023 Jul 17. https://doi.org/10.1038/s41591-023-02480-8 

Despite advances, few therapeutics have shown efficacy in severe coronavirus disease 2019 (COVID-19). In a different context, virus-specific T cells have proven safe and effective. We conducted a randomized (2:1), open-label, phase 1/2 trial to evaluate the safety and efficacy of off-the-shelf, partially human leukocyte antigen (HLA)-matched, convalescent donor-derived severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells (CoV-2-STs) in combination with standard of care (SoC) in patients with severe COVID-19 compared to SoC during Delta variant predominance. After a dose-escalated phase 1 safety study, 90 participants were randomized to receive CoV-2-ST+SoC (n = 60) or SoC only (n = 30). The co-primary objectives of the study were the composite of time to recovery and 30-d recovery rate and the in vivo expansion of CoV-2-STs in patients receiving CoV-2-ST+SoC over SoC. The key secondary objective was survival on day 60. CoV-2-ST+SoC treatment was safe and well tolerated. The study met the primary composite endpoint (CoV-2-ST+SoC versus SoC: recovery rate 65% versus 38%, P = 0.017; median recovery time 11 d versus not reached, P = 0.052, respectively; rate ratio for recovery 1.71 (95% confidence interval 1.03-2.83, P = 0.036)) and the co-primary objective of significant CoV-2-ST expansion compared to SοC (CoV-2-ST+SoC versus SoC, P = 0.047). Overall, in hospitalized patients with severe COVID-19, adoptive immunotherapy with CoV-2-STs was feasible and safe. Larger trials are needed to strengthen the preliminary evidence of clinical benefit in severe COVID-19.