Papadopoulou A, Karavalakis G, Papadopoulou E, et al. Cytotherapy. 2022; 24(5):S37–8. https://doi.org/10.1016/S1465-3249(22)00147-5

Background & Aim: SARS-CoV-2 pandemic poses an urgent need for the development of effective therapies. We report the feasibility of creating a bank of immediately available off-the-shelf SARS-CoV-2specific T cells (CoV-2-STs) from convalescents and preliminary results of a randomized phase I/II trial (EudraCT 2021-001022-22) using CoV-2- STs in high-risk COVID-19 patients.

Methods, Results & Conclusion: We prepared ~480 clinical doses of CoV-2-STs from 30 convalescent donors. Peripheral blood mononuclear cells were exposed to pepmixes spanning SARS-CoV-2 antigens (spike/membrane/NCAP) and expanded for 10 days in G-Rex to produce a median of 6x108 T-cells/donor (2-11x108). The cell products were polyclonal, enriched in CD4+ (78±2%) cells expressing memory markers and high specificity against SARS-CoV-2 [2428±109 spot forming cells (SFC)/2x105] and its variants (WT 1873±481 /alpha 2182±582/beta 2177±624 /delta 1549±463 SFC/2x105). At least 1 HLA mediating CoV-2-ST specificity was identified in 29/30 products. Hospitalized COVID-19 patients within 6 days from the symptoms onset with pneumonia, lymphopenia (CD3+≤650/ l) and ≥1 elevated biomarker (D-dimers, ferritin, CRP, LDH) were enrolled and followed for 8 weeks. Patients were evaluated for recovery by the WHO 8-point Ordinal Scale (OS). Safety was demonstrated during phase I where 6 patients received dose escalated (15x106,2x107/m2) CoV-2-STs sharing at least 1 HLA mediating specificity. In phase II, 90 randomized (2:1) high-risk patients were enrolled; 57 received the standard of care (SoC) plus partially HLA-matched CoV-2-STs and 30 received the SoC (control arm). Three withdrew consent and 1 from the CoV-2-ST arm was allocated to control arm as referred to ICU prior to receiving CoV-2-STs. On day 60 (d60) the add- on treatment resulted in 51% lower risk of mortality than SoC alone (24.6% [14/57] vs 50.0% [15/30]; risk ratio (RR): 0.49;p=0.016) with crude hazard ratio (HR) 2.42 (1.17, 5.05;p=0.018) in favor of CoV-2-STs. The benefit on survival was confirmed by multiple analysis after adjustment for confounding factors [HR:2.16(1.02, 4.60);p=0.04]. On d30, 67% had recovered (OS≤3) in the CoV-2-ST arm vs 37% in the control arm (RR, 1.82;p=0.02) with HR 0.48 (0.24, 0.94; p=0.03). CoV-2-ST-treated patients were more likely to recover by d30 even after adjustment for confounding factors [HR:0.46(0.23,0.92);p=0.03]. Overall, off the-shelf immunotherapy with CoV-2-STs can serve as a safe and effective treatment in a real world environment for severe COVID-19.