Cancer therapy shows potential to treat severe cases of Covid-19 in preclinical trials

A study published in the journal Science Advances suggests that a type of treatment known as an immune checkpoint inhibitor – already used against certain types of cancer – may be beneficial in some severe cases of Covid-19. The creators of this type of therapy, which has the ability to reactivate the immune system, won the Nobel Prize in Medicine in 2018.

The conclusions of the article are based on experiments carried out with cells from patients who had to be admitted to the Intensive Care Unit (ICU) after contracting SARS-CoV-2, as well as mice infected with another betacoronavirus, MHV-A59 (hepatitis virus). murine A59).

“One of the known immunological checkpoints that we worked with in the study is PD-1. It indicates for T lymphocytes [um tipo de leucócito] which should stop responding to the infection after a while, so that there is no exacerbated response. In the context of cancer, sepsis or severe Covid-19, however, PD-1 causes T lymphocytes to stop working before the disease even resolves. Therefore, it is necessary to block it”, explains Pedro Moraes-Vieira, a professor at the Institute of Biology at the State University of Campinas (IB-Unicamp) supported by FAPESP and one of the coordinators of the study.

The work has as one of the authors Gustavo Gastão Davanzo, a doctoral student at IB-Unicamp and a FAPESP scholarship holder.

“Although these are very expensive treatments, the fact that there are not as many serious patients as at the beginning of the pandemic makes us believe that this would be one of the viable options, if new studies show that the therapy is safe in patients with Covid-19. 19”, says Moraes-Vieira.

mouse coronavirus

The study hypothesis emerged when Uruguayan researchers – co-authors of the article – observed that mice that did not express the TMEM176D protein had more acute responses to MHV-A59 infection. This protein has the function of regulating the so-called inflammasome, a protein complex existing within defense cells that controls inflammation in an organism in order to destroy threats such as tumors, viruses and bacteria.

Without the TMEM176D protein, the inflammasome is even more activated, with greater release of inflammatory cytokines, such as interleukin-1 beta (IL-1β), whose role is known in severe Covid-19.

“This excessive release of IL-1β leads to a dysfunction of T lymphocytes, what we call the exhaustion of these defense cells. They become so activated that they can no longer respond properly. 19, something that we had already observed in a work at the beginning of the pandemic”, says Moraes-Vieira.

The work to which the researcher refers was published in 2020 in Cell Metabolism and is still among the most cited articles in the journal in the last three years, having motivated the contact of the Uruguayan team to propose the partnership.

In tests with mice, treatment with a PD-1 inhibitor was able to restore the function of T lymphocytes. In addition, the researchers had access to blood from healthy donors and from patients with Covid-19 admitted to two institutions in Montevideo, Uruguay.

Experiments with healthy cells, later infected with SARS-CoV-2, were carried out at the Laboratory for the Study of Emerging Viruses (LEVE) under the coordination of José Luiz Proença Módena, a professor at IB-Unicamp supported by FAPESP and co-author of the article.

In tests with patient samples, only cells that came from ICU patients benefited from the administration of atezolizumab, the PD-1 inhibitor drug used in the study. This is precisely because these patients have exacerbated inflammasome activation, which leads to this profile of exhaustion and dysfunction of adaptive immunity.

The researchers caution that the results still need to be viewed with caution. Studies with cancer patients who were already using the therapy before contracting Covid-19 showed no benefit or even resulted in a negative association.

In one of them, the administration of therapy before the viral infection did not lead to an improvement in the Covid-19 condition. In another study, which followed 423 patients, there were more cases of hospitalization and disease severity among those who had received the inhibitor. On the other hand, a clinical study with PD-1 inhibitors in patients with sepsis showed that the therapy is safe. New studies will therefore be needed to better understand the effects of treatment in the context of Covid-19.

The article PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical β-coronavirus disease can be read here.