A Phase I/II Study of Adoptive SARS-CoV-2 Specific T Cells in Immunocompromised Hosts with or at Risk of Severe COVID-19 Infection

Background: Post-transplant or haematological cancer patients have a higher risk of mortality after infection with ancestral and early variants of SARS-CoV-2 . Adoptive cell therapy (ACT) with virus-specific T cells could augment endogenous T cell immunity to avoid disease deterioration before viral clearance.Methods: We established a third-party SARS-CoV-2 specific T cell (COVID-T) bank in 2020 (NCT04351659) using convalescent and/or vaccinated donors. In a phase I/II study (NCT04457726), thirteen adult and paediatric patients, acutely positive for SARS-CoV-2 and predicted to have high chance of mortality, were recruited from September 2021 to February 2022. Twelve patients received a single dose of COVID-T cells, matched on at least 1 HLA. We developed a preclinical model of HLA-I deficient COVID-T cells by CRISPR/Cas9-mediated β2-microglobµlin (B2M) knockout, to minimize early rejection of third-party donor T cells for future applications.Results: A dose of either 75,000 or 150,000 IFN-γ+CD3+ cells/m2 SARS-CoV-2 specific T cells did not cause cytokine release syndrome, acute respiratory distress syndrome, or graft-versus-host disease. In the 8 patients who had detectable donor SARS-CoV-2 specific T cells after ACT, none progressed to severe disease or died with COVID-19. In contrast, among the other four patients without evidence of donor micro-chimerism, two died of COVID-19. Knock-out of HLA Class I on SARS-CoV-2 specific T cells reduced their immunogenicity without affecting phenotype or function in vitro.Interpretation: Long-acting third-party virus-specific T cells from convalescent or vaccinated donors could be expediently produced and might be clinically useful in future pandemics, particularly before global vaccination is implemented.Trial Registration: NCT04351659 & NCT04457726Funding: This study was supported by the SingHealth Duke-NUS Academic Medicine COVID-19 Research Grant (AMC/COV002/2020), Goh Foundation of Singapore and National Medical Research Council.Declaration of Interest: W.L. is a part-time employee of Miltenyi Biotec. All authors declare no competing financial interests.Ethical Approval: The two-part study was approved by the Institutional Review Board in 2020 (CIRB 2020/2198 and CIRB 2020/2562) in accordance to the declarations of Helsinki. The study was approved by the SingHealth Institutional Biosafety Committee (SHSIBC-2021-050) and authorized by the Health Sciences Authority (PRISM Application ID: 2064173C).