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ImmunoScape, Johns Hopkins Team Profiles T Cell Response in COVID-19 Patients


This story has been updated from a previous version to correct information about ImmunoScape's technology.

NEW YORK ─ A recently published study demonstrates the capabilities of Singapore-based immune profiling firm ImmunoScape's technology to characterize T cell response in patients recovered from COVID-19.

The research, published last month in the Journal of Clinical Investigation by researchers from ImmunoScape, the National Institutes of Health, and Johns Hopkins University, looked at both the viral epitopes that appear involved in T cell response as well as the phenotypes of SARS-CoV-2-specific T cells.

Its findings could help inform future design of vaccines against the virus, said study author Andrew Redd, an assistant professor at Johns Hopkins School of Medicine and a staff scientist at the National Institute of Allergy and Infectious Disease.

For the profiling work, the researchers used ImmunoScape's TargetScape assay, which uses mass cytometry to study antigen-specific CD8+ T cells. The TargetScape platform uses tetramers containing major histocompatibility complexes (MHCs) loaded with peptide antigens of interest to profile patient immune responses.

In the body, MHCs display foreign antigens on the surface of cells, activating the body's T cell response, through which the immune system kills malfunctioning or infected cells. ImmunoScape's tetramers can present the immune system with antigen peptides that may figure in conditions like cancer or infectious disease. Researchers can then monitor patterns of T cell binding to those peptides, looking for differences between, for instance, responders and non-responders to a therapy or changes in T cell binding over the course of an individual's treatment regimen.

ImmunoScape's tetramer reagents are tagged with metal barcodes that can be read out using mass cytometry, allowing investigators to multiplex hundreds of antigens of interest at a time. The mass cytometer can also analyze dozens of protein markers within and on the surface of the T cells as it reads the tetramer barcodes, allowing researchers to simultaneously collect information on T cell-antigen binding and the phenotypic and functional profiles of the bound T cells.

Redd said the approach allowed the researchers to investigate a much wider range of epitopes than would be possible with traditional T cell profiling approaches like enzyme-linked immune absorbent spot (ELISpot) assays or flow cytometry.

He said that another advantage was the ability to tag the same epitopes with two different barcodes, which improves the specificity of the assay by letting researchers require both barcodes to be detected in order to call a T cell-epitope hit. 

To do this, researchers split samples into two parts and stain each independently with different barcodes. They can then look to see if an epitope is detected in both portions of the divided sample. 

"You want to make sure that what you are seeing is actual binding and not background," he said. "Because some of these cell populations you are looking for are relatively rare. So you want to make sure that when you find that [T cell], it really is specific for that epitope and not just false binding or something like that." 

According to ImmunoScape, the company can detect cells comprising as little as .001 percent of the overall T cell population in a sample. 

Redd said one potential issue with the approach is that while it can identify T cell-epitope binding, it doesn't directly demonstrate the functionality of the bound T cells. 

"We can't do that [with the TargetScape assay] because you bind the [tetramers] to the T cells and once they are run in the [CyTOF] they are destroyed. So that is a little bit of a tradeoff," he said. 

Redd noted, though, that functional information could be inferred from the phenotype data the researchers were able to collect by measuring T cell protein markers with the platform. 

"That's the advantage of doing that characterization, of using the other 30 markers to look at the different types of cells," he said. "For example, some of our epitopes were found in effector memory cells [which] are later in development and are really meant to find defective cells and kill them. Because you get so much information, you can use that information to sort of glean what the functionality is."

In the JCI study, Redd and his colleagues used the TargetScape assay to test 408 SARS-CoV-2 epitopes for recognition by CD8+ T cells in 30 individuals who had recovered from COVID-19 while also measuring 28 T cell proteins. They identified 132 SARS-CoV-2-specific T cell responses to 52 unique epitopes, with T cell responses detected in 29 of the 30 subjects.

Among the findings was that the T cell response targeted a variety of internal and non-structural locations throughout the virus, suggesting, Redd said, that future vaccines might consider including these regions as targets to generate a broader T cell response, which he noted could help further protect against infection.

He said that he and his colleagues are now taking the data generated in the JCI work and using it to look at whether emerging SARS-CoV-2 variants, primarily the UK and South Africa variants, might escape the T cell responses they observed.

He said that only one of the 52 epitopes they identified shows alterations in the variant strains and that this alteration consists of a small mutation that is unlikely to impact binding of the epitope.

"What that suggests is that even if someone became reinfected with a new strain, the T cell responses that their body already generated after the first infection should still be highly effective in responding to the new variant," he said.

The JCI work is one of several studies ImmunoScape is conducting looking at the immune response in COVID-19 patients. While the company has focused primarily on cancer immunotherapy development, like many firms in the immunoncology space it has moved into SARS-CoV-2 research during the pandemic. The company has established collaborations with a number of firms developing vaccines for the virus, including San Diego-based Arcturus, which is currently running clinical trials in Singapore. It is also working with researchers at Massachusetts General Hospital, the University of Parma, and Duke-NUS studying immune responses to the virus.

Brian Abel, director of technical business development at ImmunoScape and an author on the JCI study, said the company is putting together data from its various collaborations to better understand the T cell response across large numbers of individuals.

"When you start compiling of the data and understanding what is responded to from the virus, you can maybe get an idea of the immunodominance — how likely you are to see an immune response against a particular epitope across a large number of subjects and also what other responses you can induce that are likely to be good for a vaccine outcome," he said.

Such information, he said, could be helpful for future rational vaccine design efforts. He said ImmunoScape has also begun studies looking at the phenotype of the T cells involved in patient response to vaccine candidates to determine links between these phenotypes and adverse reactions to vaccines that could help with safety assessments.

Abel said the company also hopes to investigate how T cell response varies with disease severity and patient outcomes, noting that while the subjects in the JCI study had mild cases, ImmunoScape is looking at a group of patients with more severe disease in its work with MGH.