Abstract
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. EudraCT identifier: 2021-001022-22.
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Data availability
George Papanikolaou Hospital is committed to responsible and transparent sharing of clinical trial data with healthcare practitioners and researchers, toward the improvement of scientific knowledge and the promotion of innovative medical approaches. Participant de-identified data collected for this study, including text, tables, figures, appendices and documents, including the study protocol, statistical analysis plan and informed consent form, will be available after article publication. Researchers interested in obtaining access to documents and/or data for academic use only can make their request by submitting the scientific design, specific data needs and analysis and dissemination plans, which will be reviewed by the institutional review board of George Papanikolaou Hospital, and, based on scientific merit, data access could be granted. An agreement will be signed between the two parties stating that the data will be used only for the agreed purpose, in compliance with ethical and regulatory requirements and the commitments made to the study participants. Any publication derived from the accessed data should be of high quality, and George Papanikolaou Hospital’s institutional review board will have the right to review and comment on any draft manuscripts before publication.
Change history
27 July 2023
In the version of this article initially published, the Abstract did not list the EudraCT identifier: 2021-001022-22 (ClinicalTrials.gov ID: NCT05447013), which is now amended in the HTML and PDF versions of the article.
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Acknowledgements
We express our sincere thanks to the donors and patients. We thank all healthcare professionals who took care of the patients on hard times. This work was supported by the Committee of ‘Greece 2021’ and George Papanikolaou Hospital. We also greatly appreciate the support of community fundraising. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Study design and development of concept: A.P. and E.Y. GMP production and quality assurance: A.P., P.-G.P, A.G., I.V. and E.Y. Patient management: G.K., E.P., Z.B., M.K., E.V., V.P., A.V., E. Serasli, I.S., A.A, S.T., M.S., Z.S., N.K., M.B., M.T., D.A., G.P., M.D. and E.Y. Data collection: E.P., Z.B., A.V., M.G., F.S., A.X., A.F., P.-G.P., A.G., I.V., M.T., M.D., P.M., T.Κ., G.C., A.B., A.P. and M.G.K. Data analysis: G.S., G.K., G. Gounelas, G. Georgolopoulos, A.P. and E.Y. Study coordination: E.Y. and A.P. Obtained funding: E.Y. and A.A. Wrote the manuscript: A.P. and E.Y. All authors reviewed and revised the final manuscript.
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Extended data
Extended Data Fig. 1
Kaplan-Meier curves for mortality (time to death) at 30 days in the modified intention-to-treat (mITT) population. P value was calculated using the two-sided log-rank test.
Extended Data Fig. 2
Subgroup analysis on mortality at 60 days, in the and mITT population. mITT: modified intention-to-treat analysis. Two-sided Wald test-based P values (as calculated using Cox regression). All P values shown are unadjusted for multiple testing and should therefore not be used to infer treatment effects.
Extended Data Fig. 3
Longitudinal analysis of T lymphocyte recovery kinetics over the study period in CoV-2-ST+SoC-treated (red lines, n = 58) and SoC-treated (blue lines, n = 29) patients. The thin lines represent individual CD3+ cell values for each patient. Bold lines are the quadratic fitted splines for each group. Shaded bands extend to 95% CI of the fitted values. Tukey HSD p-value is reported.
Extended Data Fig. 4
Correlation of the kinetics of circulating CoV-2-STs and viral load, in CoV-2-STs+SoC-treated (n = 57) and SoC-treated (n = 30) patients. The dotted lines represent the fitted values of circulating CoV-2-STs, the solid lines represent the fitted values of SARS-CoV-2 viral load. Shaded bands extend to 95% CI of fitted values. Pearson’s correlation coefficient values are reported.
Extended Data Fig. 5
Longitudinal trajectories of circulating CD4 (A) and CD8+ (B) cells in surviving (green lines, n = 58) and non-surviving (purple lines, n = 29) COVID-19 patients. Thin lines represent individual cell population counts for each patient. Bold lines are the quadratic fitted splines of each group. Shaded bands represent the 95% CI of the fitted values. One-way ANOVA p-values are reported for the survival status effect on both CD4 and CD8 trajectories.
Extended Data Fig. 6
Kaplan-Meier curve for hospitalization length at 60 days in the mITT population. P value was calculated using the two-sided log-rank test.
Supplementary information
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Supplementary Figs. 1–15, Supplementary Tables 1–10, Supplementary References, Statistical Analysis Plan and Clinical Protocol.
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Papadopoulou, A., Karavalakis, G., Papadopoulou, E. et al. SARS-CoV-2-specific T cell therapy for severe COVID-19: a randomized phase 1/2 trial. Nat Med 29, 2019–2029 (2023). https://doi.org/10.1038/s41591-023-02480-8
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DOI: https://doi.org/10.1038/s41591-023-02480-8
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