An article published in Progress of science suggests that a type of cancer treatment known as immune checkpoint blockade may be beneficial in certain cases of severe COVID-19. The creators of this therapy, which can successfully activate the immune system to fight cancer, won the 2018 Nobel Prize in Physiology or Medicine.
The findings reported by the authors were based on experiments with cells from patients treated in intensive care units (ICUs) after being infected with SARS-CoV-2 and mice infected with MHV-A59 (murine hepatitis A59 virus), another betacoronavirus.
“PD-1 blockade is one of the known immune checkpoint therapies and one of the therapies we looked at in the study. It tells the T cells [a type of white blood cell] stop responding to the infection after a while so that the response is not excessive. However, in cases of cancer, sepsis, and severe COVID-19, PD-1 causes T cells to stop working even before the disease has resolved, and therefore they must be blocked,” said Pedro Moraes- Vieira, one of the leaders of the study.
Moraes-Vieira is a professor at the Institute of Biology of the State University of Campinas (IB-UNICAMP) in São Paulo, Brazil, and is supported by FAPESP.
Another co-author is Gustavo Gastão Davanzo, a doctoral candidate at IB-UNICAMP with a scholarship from FAPESP.
These are very expensive treatments, but we think it could be a viable option because there are not as many critically ill patients as there were at the beginning of the pandemic, provided more research confirms that it is safe for COVID-19 patients.”
Pedro Moraes-Vieira, Professor, Institute of Biology of the State University of Campinas, São Paulo, Brazil
The hypothesis contrasted in the study arose when Uruguayan researchers (co-authors of the article) observed that mice that did not express the TMEM176D protein responded more acutely to MHV-A59 infection. This protein regulates inflammasomes, protein complexes deployed by the innate immune system to trigger inflammation as a weapon against tumors, viruses and bacteria.
Inflammasome activation is more intense without TMEM176D. More inflammatory cytokines are released, including interleukin-1 beta (IL-1β), which is known to play a role in severe COVID-19 (more at: agency.fapesp.br/34732/).
“Excessive release of IL-1β leads to T-lymphocyte dysfunction, which we call T-cell exhaustion,” said Moraes-Vieira. “These cells are so strongly activated that they can no longer respond properly. This is common in chronic viral diseases such as severe COVID-19, as we found in a study conducted early in the pandemic.”
An article about the study in question, published in 2020 in Cellular metabolismis one of the most cited articles published in this magazine in the last three years and motivated the Uruguayan team to propose an alliance (more at: agency.fapesp.br/33296/).
In the mouse trials, treatment with a PD-1 inhibitor restored T-cell functionality. In addition, the researchers had access to blood from healthy donors and from COVID-19 patients hospitalized at two institutions in Montevideo, capital of the United States. Uruguay.
Experiments with healthy cells infected with SARS-CoV-2 were carried out at the Laboratory for the Study of Emerging Viruses (LEVE) at UNICAMP, led by Professor José Luiz Proença Módena, co-author of the article, with the support of FAPESP.
In trials using human blood samples, only cells that came from intensive care patients benefited from the administration of atezolizumab, a PD-1 inhibitor used in the study. This was due to overactivation of the inflammasome leading to depletion and dysfunction of adaptive immunity in these patients.
The findings should be viewed with caution, the researchers caution. Studies involving cancer patients who were treated in this way before contracting COVID-19 showed no benefit or pointed to negative results.
In one study, giving the therapy before viral infection did not lead to improvement in COVID-19. In another study, involving 423 patients, there were more cases of hospitalization and severe illness among those who had received the inhibitor. On the other hand, a clinical trial of PD-1 inhibitors in patients with sepsis showed that the therapy is safe. Therefore, more research will be needed to gain a deeper understanding of treatment effects in the context of COVID-19.
São Paulo Research Foundation (FAPESP)
Vega, M.D., et al. (2022) PD-1/PD-L1 blockade abrogates a dysfunctional innate adaptive immune axis in β-coronavirus critical illness. Progress of science. doi.org/10.1126/sciadv.abn6545.
#Immune #checkpoint #therapy #beneficial #cases #severe #COVID19