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Review
. 2020 Jul 3:11:1625.
doi: 10.3389/fimmu.2020.01625. eCollection 2020.

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies

Aldo Bonaventura  1   2   3 , Alessandra Vecchié  1   3 , Tisha S Wang  4 , Elinor Lee  4 , Paul C Cremer  5 , Brenna Carey  6 , Prabalini Rajendram  7 , Kristin M Hudock  8   9 , Leslie Korbee  10 , Benjamin W Van Tassell  1 , Lorenzo Dagna  11 , Antonio Abbate  1   3
Affiliations
Review

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies

Aldo Bonaventura et al. Front Immunol. .

Abstract

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.

Keywords: COVID-19; GM-CSF; IL-6; SARS-CoV-2; cytokine release syndrome; mavrilimumab.

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Figures

Figure 1
Figure 1
GM-CSF is involved in the response to SARS-CoV-2. (A) SARS-CoV-2 induces a cytokine storm with increased levels of inflammatory mediators, including GM-CSF. GM-CSF binds the α-chain of GM-CSF receptor, while the β-chain transduces the intracellular signaling. GM-CSF promotes the polarization of macrophages to the M-1 phenotype and stimulates the activation of myeloid cells that release inflammatory cytokines, like GM-CSF. APCs release GM-CSF to stimulate the differentiation of resting T cells to active T cell subpopulations. APC-derived GM-CSF promotes further release of GM-CSF through an autocrine signal. T cell-derived GM-CSF is critical to maintain T cell functions and enhance APC activity. (B) GM-CSF is involved in the differentiation of alveolar macrophages, thus enhancing the clearance of respiratory microbes through an increase in phagocytosis and release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in a feed-forward inflammatory loop. Based on previous experiences, the early administration of a rhGM-CSF, like sargramostim, may improve the initial response against viruses, including SARS-CoV-2. (C) Mavrilimumab prevents GM-CSF from binding to the α-chain of its receptor, while gimsilumab, lenzilumab, and TJ003234 directly bind GM-CSF with the final common result of blocking the intracellular signaling. Based on the current knowledge, these agents can be used to reduce the hyperinflammation caused by SARS-CoV-2 in the course of the disease. Differently from rh-GM-CSF, these agents should be considered later in order to not negatively impact the favorable effects of GM-CSF on the immune response. APC, antigen presenting cell; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. This figure has been partially created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.
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