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Review
. 2020 Aug;20(8):507-514.
doi: 10.1038/s41577-020-0357-7. Epub 2020 Jun 23.

GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches

Frederick M Lang  1 , Kevin M-C Lee  2 , John R Teijaro  3 , Burkhard Becher  4 , John A Hamilton  5   6
Affiliations
Review

GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches

Frederick M Lang et al. Nat Rev Immunol. 2020 Aug.

Abstract

Therapeutics against coronavirus disease 2019 (COVID-19) are urgently needed. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myelopoietic growth factor and pro-inflammatory cytokine, plays a critical role in alveolar macrophage homeostasis, lung inflammation and immunological disease. Both administration and inhibition of GM-CSF are currently being therapeutically tested in COVID-19 clinical trials. This Perspective discusses the pleiotropic biology of GM-CSF and the scientific merits behind these contrasting approaches.

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Conflict of interest statement

F.M.L. is a full-time employee of Roivant. Roivant is developing gimsilumab, a mAb to GM-CSF under investigation in a phase II clinical trial for the treatment of patients with COVID-19 with lung injury or ARDS. J.R.T., B.B. and J.A.H have received consulting fees from Roivant. The employer of J.A.H. and K.M.-C.L, the University of Melbourne, has licensed patented technology relating to therapeutically targeting GM-CSF to MorphoSys AG, Germany. The employer of B.B., the University of Zurich, holds a patent on the use of neutralizing GM-CSF in acute GvHD following stem cell transplantation and has a license agreement with Humanigen Inc., which is manufacturing such a GM-CSF-neutralizing mAb.

Figures

Fig. 1
Fig. 1. GM-CSF and inflammation.
The immune response, including granulocyte–macrophage colony-stimulating factor (GM-CSF) upregulation, can be triggered when an antigen induces a ‘danger’ signal from a host cell. During this response, GM-CSF can act locally in inflamed tissue to induce the survival, proliferation and/or differentiation of myeloid cells, such as monocytes/macrophages and neutrophils. More specifically, GM-CSF can potentially do the following: activate mature myeloid cells to a pro-inflammatory phenotype with enhanced cytokine (for example, IL-1, IL-6 and tumour necrosis factor (TNF)) and chemokine (for example, CCL2, IL-8 and CCL17) secretory capacity; recruit immature myeloid cells from the circulation and aid in their terminal differentiation; and develop/stimulate dendritic cells to prime the adaptive immune response. Activated lymphocytes (for example, GM-CSF-producing T helper cells) can migrate into diseased tissue and the circulation, serving as a source of GM-CSF, thereby aiding in the recruitment and activation of new myeloid cells. GM-CSF levels can also be elevated systemically to induce ‘emergency myelopoiesis’, expanding and mobilizing immature myeloid/progenitor haematopoietic cells in the circulation and bone marrow. These GM-CSF-dependent responses thus heighten the inflammatory response in inflamed or diseased tissue. The broad range of immunological activities of GM-CSF can form part of positive-feedback loops/networks that can initiate and maintain disease-causing hyperactive or chronic immune responses. GM-CSF has also been shown to enhance antimicrobial host defence and lung barrier repair (not shown). Blue arrows mean ‘secretes’, black arrows mean ‘acts on’, dotted arrows indicate movement or differentiation and ‘host cell’ refers to various haematopoietic and non-hematopoietic cell types. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
See this image and copyright information in PMC

References

    1. Zhou Y, et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci. Rev. 2020 doi: 10.1093/nsr/nwaa041. - DOI - PMC - PubMed
    1. Hamilton JA. GM-CSF in inflammation. J. Exp. Med. 2020;217:e20190945. - PMC - PubMed
    1. Hamilton JA, Cook AD, Tak PP. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nat. Rev. Drug. Discov. 2016;16:53–70. - PubMed
    1. Humanigen. FDA approves initiation of Humanigen’s phase III study of lenzilumab in COVID-19 patients. Humanigenhttps://www.humanigen.com/press/FDA-Approves-Initiation-of-Humanigen%E2%... (2020).
    1. I-Mab Biopharma. I-Mab announces IND clearance from FDA for TJM2 to treat cytokine release syndrome (CRS) associated with severe coronavirus disease 19 (COVID-19). I-Mab Biopharmahttp://www.i-mabbiopharma.com/en/article-517.aspx (2020).

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