COVID-19 CURBSIDE CONSULTS Leonard H. Calabrese, DO Tiphaine Lenfant, MD Cassandra Calabrese, DO Department of Rheumatic and Immunologic Diseases, Department of Rheumatic and Immunologic Diseases, Department of Rheumatic and Immunologic Diseases, Orthopedic & Rheumatologic Institute, Orthopedic & Rheumatologic Institute Department Orthopedic & Rheumatologic Institute, and Cleveland Clinic of Infectious Disease, Cleveland Clinic; Assistance Department of Infectious Disease, Cleveland Clinic Publique des Hôpitaux de Paris, Université de Paris; Hôpital européen Georges Pompidou, Service de médecine interne, Paris, France Cytokine storm release syndrome and the prospects for immunotherapy with COVID-19, part 3: The role of GM-CSF Posted July 30, 2020 ■ ABSTRACT still lacking is an understanding of the precise cho- Granulocyte-macrophage colony-stimulating factor reography of cytokine storm and of which cytokine (GM-CSF) has been used experimentally in patients with or cytokines are upstream drivers vs those that may acute respiratory distress syndrome. Recombinant GM- be late-stage effectors or amplifiers. While IL-6 and CSF administered by direct inhalation is currently being IL-1 are both logical therapeutic targets and the pre- studied in a cohort of patients with advanced COVID-19. liminary data from uncontrolled studies have shown promise, inhibition has not been curative and is not ■ INTRODUCTION without real safety concerns. This Curbside Consult will focus on another cytokine of growing interest, In the first two parts of this series, we focused on the GM-CSF. basic immunobiology of severe COVID-19 disease and the role of inflammatory cytokines in driving ■ BASIC IMMUNOLOGY OF GM-CSF respiratory damage, coagulopathy, end-organ failure, and death, which is idealized in Figure 1.1,2 We know GM-CSF is a complex cytokine and a member of the that 90% of patients with COVID-19 recover, but we colony-stimulating superfamily. While it does have a are also aware that in about 10% of patients the dis- role as a growth factor for myeloid cells, this is con- ease is progressive, and that this is heavily influenced sidered a lesser function compared with other cyto- by a growing number of risk factors, including atten- kines such a granulocyte-stimulating colony factor dant cardiovascular disease, obesity, hypertension, (G-CSF) and macrophage-stimulating colony factor and age. This stage 3 of COVID-19, when the disease (M-CSF), and GM-CSF is now considered a central player in the integrated immune response and a cen- may rapidly progress to fatality, has been continuously 4,5 elucidated and referred to as “cytokine storm,” given tral mediator of tissue inflammation. the presence of elevated levels of inflammatory cyto- GM-CSF is produced by both hematopoietic (eg, kines and chemokines including interleukin 1 (IL-1), T cells, B cells, macrophages, monocytes) and some IL-6, tumor necrosis factor (TNF), granulocyte- viscerosomatic cells (type II alveolar epithelial cells, macrophage colony-stimulating factor (GM-CSF), endothelial cells, fibroblasts) and can activate cells gamma interferon, and monocyte chemotactic pro- through the dimeric GM-CSF receptor expressed tein-1 (MCP-1).2 Furthermore, quantitative studies primarily on monocytes and macrophages but also on of these biomarkers have demonstrated that some dendritic cells and other cells of the innate immune system.4,6 GM-CSF mediates its effects by signaling may discriminate mild self-limiting forms of COVID- 7 19 from severe progressive forms of the disease.3 But through the JAK-STAT pathway, a pathway inhib- ited by currently available therapeutics including tofacitinib and baricitinib. During inflammation GM- The statements and opinions expressed in COVID-19 Curbside Consults are CSF serves two important roles. First, it functions to based on experience and the available literature as of the date posted. While polarize mature myeloid cells into a pro-inflammatory we try to regularly update this content, any offered recommendations can- phenotype capable of secreting other inflammatory not be substituted for the clinical judgment of clinicians caring for individual patients. cytokines such as IL-1, IL-6, and TNF, as well as a doi:10.3949/ccjm.87a.ccc057 variety of chemokines governing trafficking of hema- CLEVELAND CLINIC JOURNAL OF MEDICINE 1 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. Figure 1. Three stages of COVID-19 disease. topoietic cells to areas of inflammation. GM-CSF The capacity of GM-CSF to amplify inflamma- also serves to activate dendritic cells to prime T cells tory response within the lung and its systemic effects, during antigen-specific responses and thus links the mediated by linking the release of upstream inflam- myeloid compartment and pathogenic T cells (TH-1 matory cytokines such as IL-1, IL-6, and TNF across and TH-17) in a positive feedback loop, capable of monocytes and macrophages and activated T cells in a propagating inflammation and tissue injury. positive feedback loop, highlight its potential impor- Of particular relevance and importance regarding tance in driving systemic inflammation and disease. the immunobiology of GM-CSF in COVID-19 disease However, as noted above, adding to the complexity is its complex role in lung homeostasis and inflam- is that GM-CSF is also a critical cytokine for healthy mation. In the healthy lung, GM-CSF has a critical pulmonary function and is necessary for the matura- role for maintaining the maturation and function of tion and maintenance of alveolar macrophages; and alveolar macrophages and surfactant metabolism5 and in some experimental models, it confers resistance to is required to maintain pulmonary function, as well viral respiratory balance, underscoring that all puta- as contributing to lung sentinel cell-mediated immu- tive inflammatory cytokines also play roles in inte- nity. GM-CSF also appears central in driving inflam- grated host defense.4 mation locally and systemically,5 and experimental The central role of GM-CSF in the inflamma- models of acute lung injury support this hypothesis, tory response and because GM-CSF appears to be demonstrating that resident alveolar macrophages upstream of other key inflammatory cytokines invites secrete a variety of inflammatory cytokines that lead targeting strategies against it in effort to down-mod- to the influx of innate cells including neutrophils, fur- ulate states of hypercytokinemia. GM-CSF levels are ther amplifying the activation of alveolar epithelial generally extremely low or undetectable in healthy cells and tissue damage.8 individuals and are detectable in blood of patients 2 CLEVELAND CLINIC JOURNAL OF MEDICINE Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. TABLE 1 Overview of anti-GM-CSF drugs, mechanisms, and studies Mechanism of action Drug Study population Phase Healthy individuals 1 TJ003234 COVID-19 1b/2 Ankylosing spondylitis 1 Gimsilumab COVID-19 2 Chronic myelomonocytic leukemia 1 Humanized immunoglobulin G1 Lenzilumab Relapsed or refractory large B-cell lymphoma 1/2 (IgG1) monoclonal antibody target- COVID-19 3 ing granulocyte-macrophage colony- stimulating factor (GM-CSF) Rheumatoid arthritis 2b Otilimab Inflammatory arthritis 2 COVID-19 2 Rheumatoid arthritis 2 Namilumab Chronic plaque psoriasis 2 Spondyloarthritis 2 Humanized IgG4 monoclonal Rheumatoid arthritis 2b antibody targeting GM-CSF receptor Mavrilimumab Giant cell arthritis 2 alpha COVID-19 2 Betac-receptor-specific, fully human IgG4 monoclonal antibody (inhibitor CSL311 Asthma 1 of IL-3-, GM-CSF-, and IL-5-mediat- ed functions) with inflammatory manifestations of COVID-19,9 and Luca et al12 described a single-center, nonrandomized, CD14+CD16+ monocytes, a rich source of GM-CSF, prospective cohort study in which 13 non-mechan- are expanded in such patients as well.10 As noted in ically ventilated patients with pneumonia, hypoxia, Table 1, GM-CSF targeting is actively being inves- and signs of systemic inflammation were treated with tigated in a variety of autoimmune diseases and has the anti-GM-CSF receptor mavrilimumab given as been successfully studied in a mouse model of cyto- single intravenous dose. They compared this group to kine release from CAR-T cells.11 Based on these data, a cohort of 26 patients treated simultaneously with investigation of targeting GM-CSF in COVID-19 has similar baseline characteristics receiving the same commenced. standard of care without mavrilimumab. At 28 days, no patients in the anti-GM-CSF group died, whereas ■ TARGETING GM-CSF IN AUTOIMMUNE AND 7 (27%) of 26 in the control group died. The agent INFLAMMATORY DISEASES AND COVID-19 was well tolerated with no infusion reactions. There is a rich pipeline of biologic therapeutics that This study, while encouraging, is cautionary on the target GM-CSF directly or that targeting the GM- basis of its design and the inherent risks of unobserved CSF receptor, and none are currently approved for confounders. Robust trials are under way and will any indication, though they are under investigation hopefully provide more definitive evidence (Table in many conditions, including rheumatoid arthritis, 2). A second single-center study from Mayo Clinic released but not yet peer-reviewed also described spondyloarthritis, giant cell arteritis, psoriasis, and 13 certain malignancies (Table 1). To date, there are impressive results. In this observational noncon- 8 clinical trials