COVID Virus–Specific T Cells: Potential Treatment of Severe COVID-19 Infection Under Study

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It may be possible to exploit T cells from healthy volunteers who have recovered from COVID-19 as a treatment for this viral infection. Researchers at the Center for Cell and Gene Therapy at Baylor College of Medicine have designed an off-the-shelf COVID virus–specific T-cell product (called ALVR109) and are now testing it in the clinical setting, according to a presentation at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1

“Vaccines for COVID-19 are in clinical trials, but therapeutic options are limited. Only one is approved by the U.S. Food and Drug Administration in the United States—remdesivir. In Europe, patients are treated with bamlanivimab based on convalescent plasma. There are supportive treatments options as well. Our group wanted to determine whether adoptively transferred T cells can provide therapeutic benefit to patients with COVID-19,” explained Spyridoula Vasileiou, PhD, of the Center for Cell and Gene Therapy, Baylor College of Medicine, Texas’s Children’s Hospital, and The Methodist Hospital. “There is an unmet medical need for effective treatments,” she added.

“The viral-specific T cells effector profile is polyclonal, polyfunctional, and cytolytic against viral targets. These cells are safe, with a lack of auto- and alloreactivity.”
— Spyridoula Vasileiou, PhD

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“We have been successful in defining a hierarchy of immunodominance and identifying candidate target antigens. We found it is feasible to expand SARS-CoV-2–specific T cells, with antiviral activity detected in both CD4-positive and CD8-positive T-cell compartments. The viral-specific T cells effector profile is polyclonal, polyfunctional, and cytolytic against viral targets. These cells are safe, with a lack of auto- and alloreactivity,” explained Dr. Vasileiou.

“At our center, we have longstanding expertise in these kinds of approaches to treat immunocompromised patients, such as patients undergoing stem cell transplantation. Given this expertise, it was only natural for us to explore this question. We had to work at great speed, and this may not be feasible for all institutions. We have the expertise and capability to move this forward, as we have done with other immune-based approaches in the past,” she explained.


More than 1,200,000 cases of COVID-19 have been recorded at the time of the ASH Annual Meeting, and about 20% of these patients will develop severe COVID-19 infection leading to acute respiratory distress syndrome and admittance to the intensive care unit, with an overall mortality reaching 3%. Risk factors for severe COVID-19 include older age (> 65 years), the presence of comorbidities (obesity, hypertension, diabetes, coronary heart disease), and an immune-compromised status (as in cancer).

COVID-19–associated mortality is much higher in patients with hematologic malignancies who develop severe COVID-19—approaching 40% in some reports. “In the allogeneic stem cell transplant population, SARS-CoV-2 infections result in mortality rates of up to 20%, according to population data from the United States,” Dr. Vasileiou stated.

“Cumulative evidence suggests that T cells can combat COVID-19 with protective effects. T-cell deficiencies have been reported in patients with COVID-19,” she continued.

Developing the Product

The first step in developing the off-the-shelf, universally applicable T-cell product was to examine endogenous T-cell immunity in healthy volunteers who recovered from COVID-19 without the need for hospitalization. The researchers examined immune activity against candidate antigens, profiled effector function, and looked at the frequency of responding donors and the magnitude of reactive cells.

“We wanted to see which viral antigens were most frequently recognized, and then we performed ex vivo expansion,” detailed Dr. Vasileiou.

“These data demonstrate the exquisite selectivity of these cells [viral-specific T cells] against the virus and support this effort for clinical use in high-risk patients with COVID-19.”
— Spyridoula Vasileiou, PhD

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They determined that the SARS-CoV-2 genomic structure is 30 kb in length and encodes 27 proteins. Two-thirds of the genome encodes for nonstructural proteins, whereas one-third encodes for four main structural proteins—spike [S], matrix [M], envelope [E], and nucleocapsid [N]—and several accessory proteins. They analyzed the immune response against 17 of these antigens.

To identify immunodominant target antigens, the investigators cultured peripheral blood mononuclear cells from convalescent donors with a mix of overlapping peptide libraries, spanning candidate structural, nonstructural, and accessory SARS-CoV-2 proteins. Viral-specific T cells were subsequently expanded with activating cytokines. Following expansion, they interrogated the immune response to each of these individual stimulating antigens.

Early Experimental Data

The cells expanded well in vitro. They comprised T cells almost exclusively that were polyclonal and polyfunctional and had memory potential. Immune reactivity was mediated by both CD4-positive and CD8-positive T cells. Superior clinical antiviral effects in vivo were associated with polyclonality and polyfunctionality.

Before they advanced these cells to clinical trials, the investigators assessed the cytolytic effects of the viral-specific T cells against COVID-infected cells. They found the viral-specific T cells were able to specifically kill viral antigen-expressing autologous targets, with no activity against noninfected autologous or allogeneic targets. The cytolytic activity of the virus-specific T cells resulted in approximately a 6% drop in SARS-CoV-2.

“These data demonstrate the exquisite selectivity of these cells against the virus and support this effort for clinical use in high-risk patients with COVID-19,” Dr. Vasileiou said.

Clinical Trial in Hospitalized Patients

Based on the preclinical data, Dr. Vasileiou and colleagues designed a clinical trial to assess the safety and clinical effects of SARS-CoV-2 viral-specific T cells in hospitalized high-risk patients. The trial has a dose-finding phase to identify the maximal tolerated dose and an expansion phase.

The 24-week study, which is now open to enrollment, will include hospitalized patients with COVID-19 with a high risk of progression to mechanical ventilation. First the run-in, dose-finding phase will test doses. Patients will receive a single infusion of ALVR109 cells at three different dose levels (1 x 107 cells, 2 x 107, and 4 x 107) and will be assessed for safety after 2 weeks up until 14 weeks. Then, 40 patients will be randomly assigned 1:1 to receive the optimized dose of ALVR109 vs the standard of care, and they will be assessed at 2 weeks for safety and clinical endpoints. Immune effects will be examined over time.

“Even though vaccines will be available, we do know that vaccination is not 100% effective. It is more likely the vaccine will not be able to boost immune responses in immunocompromised patients. This is where our therapy comes in. Viral-specific T cells can work in concert with a vaccine. We need multiple approaches for patients in such need,” Dr. Vasileiou said.

Additional Commentary

Alisa S. Wolberg, PhD

Alisa S. Wolberg, PhD

Alisa S. Wolberg, PhD, of the UNC Department of Pathology and Laboratory Medicine and UNC Blood Research Center, Chapel Hill, North Carolina, who moderated a press conference where these data were discussed, said these findings offer a glimmer of hope for the treatment of COVID-19.

“People with blood disorders may be at heightened risk for COVID-19, which can itself, trigger hematologic conditions, including thrombosis and other problems. ASH has a strong COVID-19 research agenda that identifies fundamental questions in this area. This abstract describes work in which researchers are building banks of COVID-19–specific T cells from patients who have recovered from COVID-19 and studying how to use them to treat people with COVID-19. Ultimately, it will take an integrated approach to fight this pandemic, and it will include both vaccines and treatments that directly fight the infection,” Dr. Wolberg commented. 

DISCLOSURE: Dr. Vasileiou has served as a consultant for AlloVir and received funding for SARS-CoV-2 research from AlloVir. Dr. Wolberg has received research grants from the National Institutes of Health/National Heart, Lung, and Blood Institute, Novo Nordisk, Bristol Myers Squibb, and Takeda.


1. Vasileiou S, Kuvalekar M, Workineh A, et al: Using allogeneic, off-the-shelf, Sars-Cov-2-specific T cells to treat high risk patients with COVID-19. 2020 ASH Annual Meeting & Exposition. Abstract 612. Presented December 7, 2020.