Vaccinated and Convalescent Donor–Derived Severe Acute Respiratory Syndrome Coronavirus 2–Specific T Cells as Adoptive Immunotherapy for High-Risk Coronavirus Disease 2019 Patients

Abstract

Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic poses an urgent need for the development of effective therapies for Coronavirus Disease 2019 (COVID-19). Methods We first tested SARS-CoV-2-specific T-cell (CοV-2-ST) immunity and expansion in unexposed donors, COVID-19 infected individuals (convalescent), asymptomatic PCR-positive subjects, vaccinated individuals, non-ICU hospitalized patients and ICU patients who either recovered and were discharged (ICU recovered) or had a prolonged stay and/or died (ICU critical). CoV-2-STs were generated from all types of donors and underwent phenotypic and functional assessment. Results We demonstrate causal relationship between the expansion of endogenous CoV-2-STs and the disease outcome; insufficient expansion of circulating CoV-2-STs, identified hospitalized patients at high-risk for an adverse outcome. CoV-2-STs with a similarly functional and non-alloreactive, albeit highly cytotoxic, profile against SARS-CoV-2 could be expanded from both convalescent and vaccinated donors generating clinical-scale, SARS-CoV-2-specific T-cell products with functional activity against both the unmutated virus and its B.1.1.7 variant. In contrast, critical COVID-19 patient-originating CoV-2-STs failed to expand, recapitulating the in vivo failure of CoV-2-specific T-cell immunity to control the infection. CoV-2-STs generated from asymptomatic PCR+ individuals presented only weak responses whereas their counterparts originating from exposed to other seasonal coronaviruses subjects failed to kill the virus, thus disempowering the hypothesis of protective cross-immunity. Conclusions Overall, we provide evidence on risk stratification of hospitalized COVID-19 patients and the feasibility of generating powerful CoV-2-ST products from both convalescent and vaccinated donors as an “off-the shelf” T-cell immunotherapy for high-risk patients.

SARS-CoV-2-specific T cells generated for adoptive immunotherapy are capable of recognizing multiple SARS-CoV-2 variants

“…Our observations that T cells can be generated from a small cohort of convalescent individuals to cover a large percentage of the population suggest that the manufacture of a similar repository of SARS-CoV-2-specific T cells is feasible. Other groups have also developed approaches for a T-cell immunotherapy approach to COVID-19 [36][37][38], with the first case report of a heart transplant patient who received SARS-CoV-2 specific T cell therapy recently published [39].…”

Off-the-Shelf Partial HLA Matching SARS-CoV-2 Antigen Specific T Cell Therapy: A New Possibility for COVID-19 Treatment

“…Unstimulated cells were used as negative controls. Following overnight stimulation, cells were surface stained for CD3, CD4, CD8, CD56, CD137 (4B4), CD154 ( 14 – 21 ), CD25 (BC96), CD38 (HIT2), CD69 (FN50), and HLA-DR (L243). Flow cytometry was performed using the BD Biosciences Fortessa cytometer.…”

Elucidating T Cell and B Cell Responses to SARS-CoV-2 in Humans: Gaining Insights into Protective Immunity and Immunopathology

“…An important issue that remains unresolved thus far is whether these pre-existing cross-reactive T cells will play a protective or pathologic role once the hitherto uninfected host is subsequently exposed to SARS-CoV-2 [ 32 , 33 , 34 ]. In one retrospective study, individuals with recent exposure to endemic human CoV endemic experienced a milder disease course following subsequent SARS-CoV-2 infection, and a subsequent study demonstrated that human CoV specific, SARS-CoV-2 cross-reactive CD4 T cells can be rapidly recruited into the immune response following natural SARS-CoV-2 infection and immunization, while other studies have demonstrated the sub-optimal cytotoxic activity and polyfunctional potential of endemic human CoV derived SARS-CoV-2 cross-reactive T cells [ 35 , 36 , 37 , 65 ]. Carefully designed prospective studies evaluating the clinical outcomes of SARS-CoV-2 infection in SARS-CoV-2 unexposed individuals harboring cross-reactive T cells will be necessary to provide conclusive evidence relating to the protective and/or pathological potential of cross-reactive T cells.…”

“…Reports have begun to emerge that demonstrate the potential utility of adoptive transfer therapy using ex-vivo expanded SARS-CoV-2 specific T cells [ 37 , 40 , 41 , 42 , 72 , 73 ]. One of the earliest publications in this context utilized a good manufacturing practice (GMP)-compliant methodology to, in vitro, stimulate and expand virus-specific T cells from convalescent donors using SARS-CoV-2 peptides for the purpose of adoptive immunotherapy aimed at immunocompromised patients exposed to SARS-CoV-2 [ 40 ].…”

“… Potential downstream applications of profiling bulk or virus-specific T cells in the context of SARS-CoV-2 infection and/or after COVID-19 vaccination. Reference(s) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. …”