CONFERENCE UPDATE: ASH 2020

Off-the-shelf, allogeneic SARS CoV-2 specific T-cells to treat high-risk patients with COVID-19

28 Feb 2021

Treatment options for coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited.1 Immune compromise has been identified as a major risk factor for COVID-19, resulting in reduced T-cells count with dysregulation more commonly observed in patients with severe rather than mild COVID-19.1 Apart from the United States Food and Drug Administration (FDA) approved antiviral agent remdesivir, other therapeutics such as convalescent plasma and monoclonal antibodies are authorized for emergency use only.1

So far, T-cell immunotherapy has not been attempted against RNA viruses such as SARS-CoV-2, but was previously shown to be capable of mediating the clearance of respiratory syncytial virus without producing any associated morbidity.2 In previous studies, off-the-shelf allogeneic ex vivo expanded multi virus-specific T-cells (multi-VSTs) were found to be feasible, safe and efficacious in the treatment of Epstein-Barr virus, cytomegalovirus, BK Virus, human herpes virus 6 and adenovirus infections/disease among immunocompromised individuals.1 Therefore, there is a need to explore the feasibility of developing a banked, SARS-CoV-2 specific VST to treat those at highest risk of severe COVID-19 diseases, Dr. Spyridoula Vasileiou, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston Methodist Hospital, Texas, and her team identified the immunogenic and protective SARS-CoV-2 antigens and later generated SARS-CoV-2 specific T-cells to evaluate the selectivity and safety of this VST in clinical use.1

To identify immunogenic and protective SARS-CoV-2 antigens, peripheral blood mononuclear cells (PBMCs) from recovered non-hospitalized patients with mild COVID-19 were screened for T-cell activity against overlapping peptide libraries spanning 18 structural and non-structural SARS-CoV-2 proteins.1 A total of 8 proteins including 3 structural proteins [Spike (S), Membrane (M) and Nucleoprotein (N)], 4 non-structural proteins, and an accessory protein were identified as immunodominant and selected for VST manufacturing.1 The VST culture was then supplemented with activating cytokines to generate SARS-CoV-2-specific T-cells with activity against this combination of 8 immunodominant targets.1

A mean 29±7 (mean ± standard error of mean) fold expansion of cells that were composed almost exclusively of cluster of differentiation (CD) 3+ T-cells (97.1±0.7%) with a mixture of cytotoxic (CD8+; 10.2±1.2%) and helper (CD4+; 85.5±1.8%) T-cells was achieved.1 “These cells had a phenotype consistent with effector function and memory potential, as evidenced by upregulation of the activation markers, CD69 and CD28, and expression of central and effector memory markers, with minimal programmed cell death (PD-1) or T-cell immunoglobulin mucin (TIM3) expression,” commented Dr. Vasileiou.1

Using an interferon-g (IFNg) enzyme-linked immune absorbent spot assay, all the expanded cell lines proved to be reactive against the target antigens.1 As seen from intracellular cytokine staining (ICS), the immune response was polyfunctional, mediated by both the CD4+ and CD8+ T-cell subsets, and the majority of IFNg-producing cells also produced tumor necrosis factor-alpha (TNF-a).1 SARS-CoV-2 reactive T-cells also exhibited a primarily Th1-polarized profile, where cytokines could perpetuate autoimmune responses.3 In addition, the SARS-CoV-2 VSTs were able to selectively kill viral antigen-expressing targets with no auto- nor alloreactivity, indicative of their clinical use due to selectivity and safety.1 With SARS-CoV-2 VSTs demonstrated to be feasible for treatment, a single centre, dose-finding, proof of concept, randomized clinical trial is now being planned to further assess the safety and clinical effects of SARS CoV-2 VSTs in high-risk hospitalized patients, particularly for those who underwent transplant or therapy for hematologic malignancy.1 “We were able to successfully profile SARS-CoV-2 immunity in a cohort of convalescent individuals and identify immunodominant and protective antigen candidates for clinical-based manufacturing,” concluded Dr. Vasileiou.

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