T cells

This study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.

In this study, we report the presence of a SARS-CoV-2 specific T-cell population within CD45RA^– memory T cells from the blood of convalescent donors that can be easily, effectively, and rapidly isolated by CD45RA depletion. These specific SARS-CoV-2 CD45RA^– memory T cells may be able to clear virally infected cells and confer T-cell immunity for subsequent reinfections. These cells can be stored for use in moderate and severe cases of COVID-19 patients requiring hospitalization, thereby representing an off-the-shelf living drug.

High frequencies of rapid antigen-reactive T cells were found in convalescent donors, regardless of severity of COVID-19. The feasibility of clinical-grade production of SARS-CoV-2-specific T cells overnight for therapeutics and diagnostics is revealed.

Donations from individuals who have been infected with SARS-CoV-2 with mild symptoms and have recovered retain normal T cell compartment profiles, with CD4 and CD8 memory and effector T cells specific for SARS-CoV-2 spike, nucleocapsid and membrane antigens. These virus-specific T cells (VSTs) can be isolated using Good Manufacturing Practice (GMP)-compatible selection technology and rapidly expanded in vitro using closed culture vessels and GMP-compliant reagents and medium. The mononuclear cell fraction of a single whole blood donation from a COVID-19 convalescent donor (CCD) can be used to generate up to 10¹¹ T cells within 21 days with the desired central memory phenotype as a potential new therapy for SARS-CoV-2. This offers the potential for the manufacture of a bank of HLA-matched donor T cell products for use in clinical trial and future treatment of COVID-19 patients.

SARS-CoV-2-specific T cells generated from convalescent individuals are Th1-polarized, polyfunctional and selectively able to kill viral antigen-expressing targets with no auto- or alloreactivity, indicative of both their selectivity and safety for clinical use.

HLA-restricted and SARS-CoV-2-specific CD8 T cells could be rapidly and cost-effectively prepared in large numbers from COVID-19 convalescent allogeneic donors, banked and used immediately upon request for patients with severe COVID-19.

SARS-CoV-2-reactive T cells (stimulated with a peptide library derived from various SARS-CoV-2 proteins) were isolated from the peripheral blood of convalescent COVID-19 patients and expanded in culture with IL-2/4/7. A gene knock-out rendering the cells resistant to glucocorticoids was introduced. The cells manifested Th1 cytotoxic phenotype and SARS-CoV-2 PepMix-loaded autologous peripheral blood mononuclear cells-killing capacity in vitro. The T cells were directed mostly against Spike protein. 

SARS-CoV-2 peptide-responsive T cells were expanded from peripheral blood samples of COVID-19 convalescent patients. The cells were proposed for the use in adoptive cell therapy of COVID-19. 

SARS-CoV-2 Spike-responsive T cells were expanded from peripheral blood samples of vaccinated (BNT162b2) or COVID-19 convalescent patients (recovered from symptomatic but not critical illness). Using the cell products lysis was successfully induced in a cytotoxicity assay against autologous antigen-pulsed phytohemagglutinin blasts. The T cells responded to stimulation by B.1.1.7 and B.1.351 variant peptides, as well. 

A CD8+ T cell epitope on SARS-CoV-2 N protein mediating a robust T cell response was identified. This knowledge was suggested to be utilized in T cell-based adoptive therapy of COVID-19. 

SARS-CoV-2-specific CD45RA− memory T cell administration was followed by stabilisation of inflammatory markers. Serious adverse reactions were not observed and clinical improvement (based on an ordinal scale) was noted. Sample size: 3 (low) + 3 (intermediate) + 3 (high). Dosage: 1 × 10^5 cells/kg (low) or 5 × 10^5 cells/kg (intermediate) or 1 × 10^6 cells/kg (high). Main outcome: Safety.

Modified T calls expressing a chimeric antigen receptor derived from the CR3022 antibody were prepared. The target antigen (S1 RBD peptide) activated the cells in vitro and led to interferon-γ, granzyme B/perforin, or FasL production in the CD69+ subset of cells. The CAR-T cells effectively killed target cells coated with RBD or S1 antigens in vitro and also S1-expressing cells in a murine model. 

T cells recognizing SARS-CoV-2 antigens were successfully expanded (also) from sera of COVID-19 convalescent patients. Multiple CD4-restricted viral epitopes in conserved Spike, Envelope and Nucleocapsid proteins of SARS-CoV-2 were identified. Thus, T cell therapy (after proper MHC matching) was hypothesized to be used as a prevention or an early treatment in immunocompromised patients. 

The treatment was safe. The administration of the formulation was followed by decrease (with some variability) of viral loads and alleviation of symptoms (with pulmonary functions not completely returning to the baseline status). Corticosteroid dosing was intentionally lowered during the T cell therapy course. Sample size: 1. Dosage: 2×10^7 cells once every 14 ± 4 days (3 doses total). 

Infusions of regularory T cells from cord blood (expanded in vitro) were followed by a decrease in markers of inflammation. The treated patients recovered, although other procedures might had contributed to this outcome. Sample size: 2. Dosage: 2–3 doses of 10^8 cells 3 or 4 days apart. 

Modified T cells expressing a chimeric antigenic receptor were mathematically modelled to target SARS-CoV-2. 

Anti-SARS-CoV-2 T cells were identified in convalescent sera using virus-specific peptides. The cells were shown to be able to replicate and displayed targeted cytotoxic activity in vitro. 

Peripheral blood mononuclear cells from COVID-19 convalescent individuals were used for expansion of T cells responding to SARS-CoV-2 antigen stimulation. The T cells displayed cytotoxicity against HLA-matched cells producing SARS-CoV-2 antigens. In vitro experiments suggest efficacy against alpha and beta strains and epitope conservation suggests efficacy against gamma and delta strains. Amino acid changes were noted for selected epitopes in Omicron strain. 

T cells isolated from blood of convalescent and vaccinated individuals (BNT162b2) were expanded (using SARS-CoV-2 M protein stimulation) in vitro. The T cells displayed cytotoxicity against cells producing SARS-CoV-2 M protein. 

T cells reactive to SARS-CoV-2 antigens were selected from peripheral blood mononuclear cells from COVID-19 convalescent donors. The T cells were shown to have cytotoxic activity against SARS-CoV-2 antigen producing cells in vitro even after the T cells were genetically made to be tacrolimus resistant (this property was introduced for a potential use of the therapy in solid organ transplant patients). The T cells responded to S1 and S2 derived peptides from Alpha, Beta, Delta, and Omicron variants. 

T cells reactive to SARS-CoV-2 antigens were selected and expanded from peripheral blood mononuclear cells from COVID-19 convalescent donors using artificial antigen presenting cells. The T cells responded to SARS-CoV-2. 

T cells reactive to SARS-CoV-2 antigens were selected and expanded from peripheral blood mononuclear cells from COVID-19 convalescent donors. The T cells displayed antigen specificity for SARS-CoV-2. 

In a juvenile patient experiencing severe immunodeficiency after hematopoietic stem cell transplantation and COVID-19, decrease in viral load, expansion of CD3 lymphocytes and clinical/radiological improvement were observed after treatment with CD45RO+ memory T cells, remdesivir, and regdanvimab. Sample size: 1. Dosage: 10^6 cells/kg. 

Engineered CD8 T cells expressing ACE2-derived chimeric antigen receptor (CAR) and anti-CD3 scFv (termed “ACE2-Bite”) neutralized SARS-CoV-2 (including Delta and Omicron) and targeted infected cells in vitro. The T cells did not display off-target cytotoxicity.