Novel T-cell therapy shows promise to treat COVID-19 in high-risk patients
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An off-the-shelf, virus-specific T-cell therapy demonstrated proof of concept to enter a clinical trial for the treatment of severe COVID-19 infection, according to study results presented at the virtual ASH Annual Meeting and Exposition.
“The impact of COVID-19 disease has been tremendous so far, with almost 53 million confirmed cases worldwide as of November and cases surpassing 10 million in the United States as of early December,” Spyridoula Vasileiou, PhD, researcher at the Center for Cell and Gene Therapy at Baylor College of Medicine, said during a presentation. “Approximately 20% of infected patients develop severe disease that can lead to respiratory or multiorgan failure, while older age and other comorbidities such as obesity, diabetes and [being immunocompromised] have been identified as major risk factors associated with poor outcomes,” Vasileiou said. “Specifically, mortality rates [among] immunocompromised transplant patients have been as high as 20% and treatment options so far are limited, with only one FDA-approved antiviral agent. [Meanwhile], other modalities, such as convalescent plasma and monoclonal antibodies, have been granted emergency use authorization. There remains an unmet medical need for effective treatment options.”
Data are mounting on the protective role of T cells in those exposed to SARS-CoV-2, with individuals with more severe cases of COVID-19 more likely to have T-cell deficits or deficiencies.
Vasileiou and colleagues previously demonstrated the feasibility, safety and clinical activity of off-the-shelf virus-specific T cells to treat viral infections and/or diseases associated with a range of viruses, including BK virus, cytomegalovirus and others.
Based on their prior work, this group of researchers sought to examine the potential of targeting COVID-19 using off-the-shelf T cells that recognized SARS-CoV-2.
As a source of protective virus-specific T cells, researchers used peripheral blood mononuclear cells from convalescent individuals who had been exposed to and naturally cleared the virus using their own immune systems. To determine which particular viral proteins induced these protective T cells responsible for viral elimination, Vasileiou and colleagues examined the immunogenicity of 17 antigens and identified a combination of structural and nonstructural proteins that were immunodominant and were, thus, advanced for virus-specific T-cell production in the laboratory.
Using their robust manufacturing platform, researchers were consistently able to selectively amplify these COVID-19-specific T cells, achieving a mean 9.3-fold (± 1.1) expansion of virus-specific T cells in eight donors tested. The expanded populations were comprised almost entirely of CD3+ T cells (97.1%), with a combination of cytotoxic CD8+ (10.2%) and helper CD4+ (85.5%) T cells whose phenotype exhibited a profile consistent with the capacity for viral elimination — as evidenced by expression of CD25, CD69 and CD28 — and memory potential, researchers noted.
“When we examined the effector profile of reactive cells, we found that they were polyclonal, polyfunctional and cytolytic against viral targets with no autoreactivity or alloreactivity,” Vasileiou said.
“This provides preclinical evidence of the safety and potential for clinical benefit associated with the infusion of these off-the-shelf virus-specific T cells,” she told Healio.
Vasileiou and colleagues are now conducting a dose-finding, proof-of-concept, single-center, randomized study to assess the safety and efficacy of the COVID-19 virus-specific T-cell therapy in 40 high-risk patients.
“The trial, which is sponsored by AlloVir, will be performed in two phases,” she said. “We will have a run-in phase to identify the maximum tolerated dose of virus-specific T-cells, and we plan to test three different cell doses. Subsequently, we will advance to the randomized phase, where patients will either receive standard of care alone or standard of care plus virus-specific T cells. The primary endpoint will be safety, but we will also examine the clinical effect of the therapy using the WHO ordinal scale to grade patient status on a daily basis while they are hospitalized. Finally, we will examine the immune effects and persistence of the infused cells over time. This trial recently opened and is actively recruiting patients.”
Perspective
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Joshua A. Hill, MD
This critically important study leverages advances in T-cell therapeutics from the fields of infectious diseases and cancer immunotherapy. The proposed clinical trial using COVID-19-specific T cells in patients hospitalized with COVID-19 who are at high risk for progressive disease is particularly important for immunocompromised patients, who may be unable to mount an effective immune response and in whom the currently available therapeutic agents may be less effective.
We are entering a golden age in which technological advances have allowed for novel approaches to manage difficult-to-treat infections with targeted immunotherapies. A positive result from this trial will be important for this terrible disease and, more broadly, for this treatment paradigm of adoptive immunotherapy for infectious diseases.
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Vasileiou S, et al. Abstract 612. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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