Physicians and researchers have had questionable success treating patients with severe COVID-19 with either antibody-based drugs or convalescent plasma. Neither of those strategies is a cell-based therapy, and, in a preprint posted October 26 on bioRxiv, researchers propose collecting SARS-CoV-2–specific memory T cells from recovered individuals, banking the cells, and infusing them into patients as a treatment for infections.
“There are data now that are coming out from the analysis of the immune response that are suggesting that the T cells are more important for protection than antibodies,” says Antonio Bertoletti, who studies the development of immunological therapies at Duke-NUS Medical School in Singapore and did not participate in the work. There is therefore a rationale to use T cells to control the disease, he adds.
Previously, researchers had attempted memory T cell therapy to suppress cytomegalovirus and Epstein Barr virus. The recipients were leukemia patients who received a stem cell transplant to treat their cancer at the same time. It was this success, combined with the T cell findings from COVID-19 patients, that led Antonio Pérez-Martínez, a pediatrician at Hospital Infantil Universitario La Paz in Madrid, and his colleagues to consider a cell-based treatment for the coronavirus.
The researchers isolated memory T cells, including some that released interferon gamma, a cytokine necessary for anti-viral immunity, upon exposure to SARS-CoV-2 antigens, from the blood of people who recovered from COVID-19. They showed that it was possible to freeze, store, and thaw these cells and propose that biobanks of memory T cells could be created from convalescent donors to be infused to treat disease. The practice of storing convalescent plasma, which includes antibodies but no immune cells, to treat COVID-19 patients is already in wide use, although with mixed data on its utility.
“If you give plasma and antibodies, those antibodies could potentially fight COVID, but they are not produced in that person, so they are just have a normal half-life and they are cleared,” says Rory de Vries, an immunologist at Erasmus University Medical Center in the Netherlands who did not participate in the study. But when T cells encounter a virus, “they start expanding, and you might actually build your own new immunological memory while you’re doing that, which will never happen with plasma.”
Despite the theoretical potential, “it’s not an easy approach,” de Vries cautions. For one thing, the authors “don’t only store SARS-CoV-2 specific T cells, they store every memory cell, so that means that you also store your memory for measles or . . . previous vaccinations,” he tells The Scientist. “And if you infuse these T cells, I don’t think we really know what might happen.”
In a cell-based treatment, there are also concerns about immunological compatibility of the donor and recipient, just as there would be during an organ transplant, de Vries explains. The authors did characterize memory T cells based on human leukocyte antigens (HLA), molecules responsible for the immune system’s ability to distinguish self and non-self. But de Vries cautions that HLA diversity is vast, potentially requiring more extensive characterization than the authors have done in the preprint to make the treatment safe.
According to Pérez-Martínez, the HLA matching is sufficient because patients with severe COVID-19 have lymphopenia, a dearth of white blood cells called lymphocytes, a subtype of which are T cells. Lymphopenia is a biological marker of severe COVID-19, he says. The patients who are more lymphopenic have a greater chance of ending up in the ICU and eventually dying.
The lymphopenia triggered by the coronavirus is similar to the lymphopenia induced by chemotherapy drugs in patients before a stem cell transplant, so the transplant won’t be rejected, he explains. This “lymphopenic window” during COVID-19 is the time at which it could be possible to replace a patient’s missing lymphocytes with SARS-CoV-2-responsive T cells from recovered donors. The idea is that lymphopenic patients don’t have enough of their own T cells, so they’re not going to reject donor lymphocytes.
This strategy “is complicated and needs some work,” says Bertoletti. “It could be that for a short time . . . when you are introducing these T cells in a patient, they will be basically able to suppress viral replication and kill the infected cells,” he adds, but the unanswered questions of how important HLA matching is and what the appropriate timing for such a treatment complicates matters.
In order to test the safety of the treatment, Pérez-Martínez and colleagues are beginning a Phase I clinical trial in patients hospitalized for COVID-19 with lymphopenia. In the transplant setting, doctors have not seen any side effects, he says, “so I think that it’s worth it to try.”
C. Ferreras et al., “SARS-CoV-2 specific memory T lymphocytes from COVID-19 convalescent donors: identification, biobanking and large-scale production for Adoptive Cell Therapy,” bioRxiv, doi:10.1101/2020.10.23.352294, 2020.