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

Introduction: Endogenous 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.
Methods: We 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.
Results: We 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.
Discussion: We 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.
Competing Interests: HL is a paid consultant to Partner Therapeutics and has stock options. KP, TB, and CR, are employees of Partner Therapeutics and have stock options. ER at the time of drafting of this manuscript was an employee of Partner Therapeutics and has stock options. TW, EB, MD, RP, and RG received funds from Partner Therapeutics within the past 3 years, but none in relation to this publication. HL is a paid consultant to Pluri-Biotech, Inc. TW acknowledges support from Savara, Kiniksa, Kinevant (for participation on a DSMB or advisory board), the PAP Foundation (serves as the vice president and clinical director of the PAP Foundation) and is a paid consultant to IQVIA. EL acknowledges funding from the NIH, myCME, is a paid consultant to Guidepoint Global, and received support for travel from the PAP Foundation. EB acknowledges support from Genentech, Novartis, and Lilly, and received funds from Apexigen, Shionogi, Bristol Myers Squibb, Nektar, Instilbio, and Xilio for consulting within the past 3 years. MD received funds from Neolukin Therapeutics (and has stock options), Moderna, Aditum, OREC, Tillotts Pharma, SQZ Biotech, AzurRx, and Mallinckrodt for consulting within the past 3 years, and acknowledges support from UpToDate, Sandoz Academy, Experts at Your Fingertips, and WebMD. DA acknowledges funding from the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. RP acknowledges support to his institution from the US Department of Veterans Affairs and the NHLBI. RG is a consultant to NexImmune Inc., Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, and a Medical Director within FFF Enterprises Inc. and AZAC Inc. RG serves on the Board of Directors of the Russian Foundation for Cancer Research Support and is on the Scientific Advisory Board of StemRad Ltd.
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