Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor inhibitors may be a potential treatment option for cytokine release syndrome in coronavirus disease 2019 (COVID-19), according to a recent report published in Lancet Rheumatology.1
During an evaluation of the association between the COVID-19-causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the immune system, investigators identified a massive release of proinflammatory mediators linked to an aberrant immune response that strongly resembled the response to the use of chimeric antigen receptor T cells in cancer therapy called cytokine release syndrome.2 This condition typically results in a high concentration of interleukin (IL)-6; therefore, researchers have hypothesized that the use of IL-6 inhibitors may be a potential treatment for severe SARS-CoV-2 infection. In addition, the anti-IL-6 agent tocilizumab is still being tested in trials for the treatment of severe COVID-19, though its effectiveness is not confirmed yet.
In this report, Favalli and Caporali have referred to recent study findings published in Lancet Rheumatology3 that have indicated an important advance for COVID-19 treatment using mavrilimumab, a GM-CSF receptor inhibitor. This study enrolled nonmechanically ventilated patients with COVID-19 pneumonia and systemic hyperinflammation. At the 28-day follow-up, the investigators of the study observed that all 13 patients treated with mavrilimumab compared with 17 of the 26 patients receiving standard treatment, including hydroxychloroquine, azithromycin, and lopinavir-ritonavir, showed clinical improvement (P =.030). None of the patients compared with 7 of them treated with mavrilimumab and standard treatment died, respectively.
Favalli and Caporali noted that this study had several limitations including low sample size, lack of randomization, and short follow-up time. However, they highlighted that the research included a more well-matched control group than other similar studies investigating tocilizumab or anakinra for COVID-19 treatment.
Another recent study4 strengthened the results reported by De Luca and colleagues. Chinese researchers observed atypical pathogenic T helper 1 cells that expressed GM-CSF in patients with severe SARS-CoV-2 infection, which may confirm the crucial role of GM-CSF in the pathogenesis of SARS-CoV-2-related hyperinflammation.
Favalli and Caporali also commented on the safety of mavrilimumab for the treatment of SARS-CoV-2 infection. While there are concerns about the development of pulmonary proteinosis because of the role of GM-CSF in the clearance of the alveolar surfactant by resident macrophages, there may be an overall favorable safety profile of mavrilimumab in patients with SARS-CoV-2.
“GM-CSF receptor blockade is certainly a potential option for the treatment of more severe subsets of COVID-19, and more extensive studies are warranted to confirm the role of GM-CSF in the pathogenesis of cytokine release syndrome,” the authors of the report concluded.
1. Favalli EG and Caporali R. GM-CSF in the treatment of COVID-19: a new conductor in the pathogenesis of cytokine storm? [published online June 16, 2020]. Lancet Rheumatol. doi:10.1016/ S2665-9913(20)30185-5
2. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6:56.
3. De Luca G, Cavalli G, Campochiaro C, et al. GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study [published online June 16, 2020]. Lancet Rheumatol. doi:10.1016/S2665-9913(20)30170-3
4. Zhou Y, Fu B, Zheng X, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients [published March 13, 2020]. Natl Sci Rev. doi:10.1093/nsr/nwaa041