CONFERENCE UPDATE: ASH 2020
Off-the-shelf, allogeneic SARS CoV-2 specific T-cells to treat high-risk patients with COVID-19
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.
Protecting children from the looming threat of MIS-C during the COVID-19 pandemic
Multisystem inflammatory syndrome in children (MIS-C) is a novel post-infectious inflammatory condition associated with Coronavirus disease 2019 (COVID-19), characterized by prolonged fever, gastrointestinal (GI) symptoms and rash.1 To some extent, the disease resembles Kawasaki disease (KD), toxic shock syndrome (TSS), and hemophagocytic lymphohistiocytosis (HLH), increasing the difficulty in differential diagnosis in clinical practice.1 In an interview with Omnihealth Practice, Dr. Cheung, Wai-Yin Eddie discussed the challenge of evaluating suspected MIS-C cases in real-life scenarios and emphasized the importance of timely intervention among children who were infected with or recently recovered from COVID-19. He also shared a clinical case of a 7-year-old girl with MIS-C who presented with early MIS-C symptoms and was managed with immunomodulatory treatment, swiftly achieving favorable outcomes.
Early molnupiravir and nirmatrelvir-ritonavir show substantial clinical benefits in local hospitalized COVID-19 patients
In a local retrospective cohort study analyzing data during Hong Kong’s omicron BA.2 wave, molnupiravir and nirmatrelvir-ritonavir were found to be effective in reducing the risks of all-cause mortality and disease progression, as well as the need for oxygen therapy among hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without supplemental oxygen requirement.1 The study revealed the substantial clinical benefits of oral antivirals, supporting their early use among Coronavirus disease 2019 (COVID-19) patients in Hong Kong.1
BNT162b2 boosters and beyond: Strategies to overcome waning immune responses against omicron variant
During the fifth wave of Coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [B.1.1.529 (Omicron), predominant] infected over a million people and claimed more than 9,000 lives in Hong Kong.1 Elderly people aged ≥60 years were the most vulnerable population and accounted for ≥95% of the total death cases.1 Among the deceased, most were unvaccinated (>70%), or had received only 1 dose of COVID-19 vaccine, and/or were with known chronic diseases.1 Even for people who have received 2 doses of vaccines, increasing evidence showed that protection against severe COVID-19 would be reduced due to the waning immune responses against the Omicron variant.2 As such, in an interview with Omnihealth Practice, Professor HUNG, Fan-Ngai Ivan, addressed the rising concern about Omicron and presented the latest data showing that BNT162b2 boosters are still highly effective against the new threat. He also provided some updates on the development of new Omicron-adapted vaccines for conferring better protection to people.
Long-term neurologic symptoms emerge in 1 out of 3 patients hospitalized with COVID-19
With confirmed cases of the 2019 coronavirus disease (COVID-19) on the rise, neurological symptoms and syndromes have been reported by a significant proportion of patients in addition to the predominant respiratory symptoms.1-3 A recent study from Italy further demonstrated that long-term neurologic
Decreasing seroprevalence of immunoglobulin M AND G antibodies against SARS-cov-2 away from epicentre Wuhan
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has given rise to the ongoing coronavirus disease 2019 (COVID-19) pandemic, is highly contagious and can lead to high morbidity and mortality rates.1,2 A recent study published in Nature Medicine used data of host