Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

Abstract

IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

Gas Plasma Exposure Alters Microcirculation and Inflammation during Wound Healing in a Diabetic Mouse Model

“…The present study further suggests that the granulocyte-macrophage colony-stimulating factor (GM-CSF or CSF2) is required in cutaneous wound healing, particularly at early stages. GM-CSF is a cytokine that promotes angiogenesis during wound healing by stimulating endothelial cell proliferation [70] and migration [71,72], increasing vascular permeability [73], inducing the production of angiogenic factors [74], and recruiting pro-angiogenic cells [75]. These effects collectively contribute to forming a new vascular network, supporting tissue repair and regeneration.…”

Knowledge mapping of COVID-19 and autoimmune diseases: a visual and bibliometric analysis

“…ARDS is a serious disease caused during the progression of COVID-19, which can be caused by cytokine storm and is associated with high mortality [ 80 , 81 ]. Endogenous GM-CSF deficiency or insufficiency may be associated with a variety of infections, including autoimmune alveolar proteinosis (aPAP), wound healing, and anticancer immune checkpoint inhibitor therapy [ 82 ]. Finally, regarding the blood–brain barrier, the cytokine storm and hypoxia conditions mentioned above may lead to the destruction of the blood–brain barrier, abnormal coagulation and autoimmune neuropathy [ 83 ].…”

Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer

“…At first, GM-CSF was recognized for its effects on hematopoiesis, particularly the myeloid lineage, that included the proliferation, activation, maturation, and differentiation of committed hematopoietic progenitors (Figure 3) [36,40]. Subsequently, GM-CSF has been demonstrated to be an immunomodulatory cytokine that can have more widespread effects [36,[41][42][43][44]. GM-CSF is mainly produced by T helper (CD4 + ) lymphocytes and innate lymphoid cells; the nonhematopoietic cell populations, which are able to secrete GM-CSF in response to specific stimuli, include fibroblasts, endothelial cells, and alveolar epithelial cells [45,46].…”

“…ICI-induced inflammation and immune response dysregulation may damage GM-CSF-producing GI tract tissues in immune-mediated colitis as well as lung tissue in checkpoint-induced pneumonitis [14,97]. The use of rhu GM-CSF may mitigate moderate-to-severe immune-related adverse events (irAEs), including GI irAEs; this approach additionally may provide a survival benefit [42,45].…”

“…In addition, the lower rates of colonic perforation support the role that GM-CSF plays in protecting against colitis and GI irAEs due to ICI therapy. Additionally, GM-CSF can drive the differentiation of dendritic cells and improve anti-tumor immunity in some settings, although this effect appears to be dose-dependent [36,[41][42][43]. It is also possible that part of the positive response of GM-CSF therapy in Crohn's disease and in ICI-induced enterocolitis is through a better defense against invading microbes and an enhancement of wound healing [42].…”