Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease
Huntington Potter, Jonathan H Woodcock, Timothy D Boyd, Christina M Coughlan, John R O'Shaughnessy, Manuel T Borges, Ashesh A Thaker, Balaibail A Raj, Katarzyna Adamszuk, David Scott, Vanesa Adame, Paige Anton, Heidi J Chial, Helen Gray, Joseph Daniels, Michelle E Stocker, Stefan H Sillau, Huntington Potter, Jonathan H Woodcock, Timothy D Boyd, Christina M Coughlan, John R O'Shaughnessy, Manuel T Borges, Ashesh A Thaker, Balaibail A Raj, Katarzyna Adamszuk, David Scott, Vanesa Adame, Paige Anton, Heidi J Chial, Helen Gray, Joseph Daniels, Michelle E Stocker, Stefan H Sillau
Abstract
Introduction: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology.
Methods: A randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments.
Results: Sargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo.
Discussion: The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted.
Keywords: Alzheimer's disease; Mini‐Mental State Examination; Pittsburgh compound B positron emission tomography; activities of daily living; amyloid; cytokine; glial fibrillary acidic protein; granulocytemacrophage colony stimulating factor; granulocyte‐macrophage colony‐stimulating factor; innate immune system; interleukin‐6; lymphocyte; monocyte; neuroinflammation; neutrophil; sargramostim; tau; tumor necrosis factor‐alpha; ubiquitin C‐terminal hydrolase L1.
Conflict of interest statement
Drs. Potter and Boyd are two of the inventors on several U.S. patents owned by the University of South Florida, but not licensed. As of Feb.1 2021, Dr. Boyd is an employee of Partner Therapeutics.
© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.
Figures
References
- Potter H. Beyond beta protein—the essential role of inflammation. Prominent Press; 2001.
- Andreasson KI, Bachstetter AD, Colonna M, et al. Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem. 2016;138:653‐693.
- Frost GR, Jonas LA, Friend LiYM. Foe or Both?. Immune Activity in Alzheimer's Disease. 2019;11:337.
- Nichols MR, St‐Pierre MK, Wendeln AC, et al. Inflammatory mechanisms in neurodegeneration. J Neurochem. 2019;149:562‐581.
- McGeer PL, Schulzer M, McGeer EG. Arthritis and anti‐inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology. 1996;47:425‐432.
- McGeer PL, Rogers J, McGeer EG. Inflammation, anti‐inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis. 2006;9:271‐276.
- ADAPT_FS_Research_Group. Follow‐up evaluation of cognitive function in the randomized Alzheimer's disease anti‐inflammatory prevention trial and its follow‐up study. Alzheimers Dement. 2015;11:216‐225.e1.
- Boyd TD, Bennett SP, Mori T, et al. GM‐CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. Journal of Alzheimer's disease : JAD. 2010;21:507‐518.
- Kiyota T, Machhi J, Lu Y, et al. Granulocyte‐macrophage colony‐stimulating factor neuroprotective activities in Alzheimer's disease mice. J Neuroimmunol. 2018;319:80‐92.
- Castellano JM, Mosher KI, Abbey RJ, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature. 2017;544:488‐492.
- Jim HS, Boyd TD, Booth‐Jones M, Pidala J, Potter H. Granulocyte macrophage colony stimulating factor treatment is associated with improved cognition in cancer patients. Brain disorders & therapy. 2012;1:1000101.
- Buschmann IR, Busch HJ, Mies G, Hossmann KA. Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte‐macrophage colony‐stimulating factor. Circulation. 2003;108:610‐615.
- Nakagawa T, Suga S, Kawase T, Toda M. Intracarotid injection of granulocyte‐macrophage colony‐stimulating factor induces neuroprotection in a rat transient middle cerebral artery occlusion model. Brain Res. 2006;1089:179‐185.
- Schneider UC, Schilling L, Schroeck H, Nebe CT, Vajkoczy P, Woitzik J. Granulocyte‐macrophage colony‐stimulating factor‐induced vessel growth restores cerebral blood supply after bilateral carotid artery occlusion. Stroke. 2007;38:1320‐1328.
- Todo K, Kitagawa K, Sasaki T, et al. Granulocyte‐macrophage colony‐stimulating factor enhances leptomeningeal collateral growth induced by common carotid artery occlusion. Stroke. 2008;39:1875‐1882.
- Kong T, Choi JK, Park H, et al. Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte‐macrophage colony‐stimulating factor in rats. Laboratory investigation. J Neurosurg. 2009;111:155‐163.
- Theoret JK, Jadavji NM, Zhang M, Smith PD. Granulocyte macrophage colony‐stimulating factor treatment results in recovery of motor function after white matter damage in mice. Eur J Neurosci. 2016;43:17‐24.
- Chung J, Kim MH, Yoon YJ, Kim KH, Park SR, Choi BH. Effects of granulocyte colony‐stimulating factor and granulocyte‐macrophage colony‐stimulating factor on glial scar formation after spinal cord injury in rats. J Neurosurg Spine. 2014;21:966‐973.
- Huang X, Kim JM, Kong TH, et al. GM‐CSF inhibits glial scar formation and shows long‐term protective effect after spinal cord injury. J Neurol Sci. 2009;277:87‐97.
- Shultz SR, Tan XL, Wright DK, et al. Granulocyte‐macrophage colony‐stimulating factor is neuroprotective in experimental traumatic brain injury. J Neurotrauma. 2014;31:976‐983.
- Kelso ML, Elliott BR, Haverland NA, Mosley RL, Gendelman HE. Granulocyte‐macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma. J Neuroimmunol. 2015;278:162‐173.
- Schallenberg M, Charalambous P, Thanos S. GM‐CSF protects rat photoreceptors from death by activating the SRC‐dependent signalling and elevating anti‐apoptotic factors and neurotrophins. Graefes Arch Clin Exp Ophthalmol. 2012;250:699‐712.
- Legacy J, Hanea S, Theoret J, Smith PD. Granulocyte macrophage colony‐stimulating factor promotes regeneration of retinal ganglion cells in vitro through a mammalian target of rapamycin‐dependent mechanism. J Neurosci Res. 2013;91:771‐779.
- Kim JK, Choi BH, Park HC, et al. Effects of GM‐CSF on the neural progenitor cells. Neuroreport. 2004;15:2161‐2165.
- Kruger C, Laage R, Pitzer C, Schabitz WR, Schneider A. The hematopoietic factor GM‐CSF (granulocyte‐macrophage colony‐stimulating factor) promotes neuronal differentiation of adult neural stem cells in vitro. BMC Neurosci. 2007;8:88.
- Huang X, Choi JK, Park SR, et al. GM‐CSF inhibits apoptosis of neural cells via regulating the expression of apoptosis‐related proteins. Neurosci Res. 2007;58:50‐57.
- Choi JK, Kim KH, Park H, Park SR, Choi BH. Granulocyte macrophage‐colony stimulating factor shows anti‐apoptotic activity in neural progenitor cells via JAK/STAT5‐Bcl‐2 pathway. Apoptosis. 2011;16:127‐134.
- Krieger M, Both M, Kranig SA, et al. The hematopoietic cytokine granulocyte‐macrophage colony stimulating factor is important for cognitive functions. Sci Rep. 2012;2:697.
- Taipa R, das Neves SP, Sousa AL, et al. Proinflammatory and anti‐inflammatory cytokines in the CSF of patients with Alzheimer's disease and their correlation with cognitive decline. Neurobiol Aging. 2019;76:125‐132.
- Verma N, Beretvas SN, Pascual B, Masdeu JC, Markey MK. New scoring methodology improves the sensitivity of the Alzheimer's disease assessment scale‐cognitive subscale (ADAS‐Cog) in clinical trials. Alzheimers Res Ther. 2015;7:64.
- Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata‐driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377‐381.
- PartnerTherapeuticsInc. Leukine [package insert]. Lexington, MA2018.
- Damiani G, McCormick TS, Leal LO, Ghannoum MA. Recombinant human granulocyte macrophage‐colony stimulating factor expressed in yeast (sargramostim): a potential ally to combat serious infections. Clin Immunol. 2020;210:108292.
- Borriello F, Galdiero MR, Varricchi G, Loffredo S, Spadaro G, Marone G. Innate immune modulation by GM‐CSF and IL‐3 in health and disease. Int J Mol Sci. 2019;20:834.
- Evans S, McRae‐McKee K, Wong MM, Hadjichrysanthou C, De Wolf F, Anderson R. The importance of endpoint selection: how effective does a drug need to be for success in a clinical trial of a possible Alzheimer's disease treatment?. Eur J Epidemiol. 2018;33:635‐644.
- Roberts C, Torgerson DJ. Understanding controlled trials: baseline imbalance in randomised controlled trials. Bmj. 1999;319:185.
- Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15‐week, double‐blind, placebo‐controlled study. Donepezil study group. Arch Intern Med. 1998;158:1021‐1031.
- Jack CR Jr, Bennett DA, Blennow K, Research Framework NIA‐AA. Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:535‐562.
- Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid‐β biomarkers for Alzheimer's disease. Nature. 2018;554:249‐254.
- Janelidze S, Stomrud E, Palmqvist S, et al. Plasma β‐amyloid in Alzheimer's disease and vascular disease. Sci Rep. 2016;6:26801.
- Lue LF, Sabbagh MN, Chiu MJ, et al. Plasma levels of Aβ42 and tau identified probable Alzheimer's Dementia: findings in two cohorts. Front Aging Neurosci. 2017;9:226.
- Öhrfelt A, Johansson P, Wallin A, et al. Increased cerebrospinal fluid levels of ubiquitin carboxyl‐terminal hydrolase l1 in patients with Alzheimer's disease. Dement Geriatr Cogn Dis Extra. 2016;6:283‐294.
- Wang KK, Yang Z, Sarkis G, Torres I, Raghavan V. Ubiquitin C‐terminal hydrolase‐L1 (UCH‐L1) as a therapeutic and diagnostic target in neurodegeneration, neurotrauma and neuro‐injuries. Expert Opin Ther Targets. 2017;21:627‐638.
- Klunk WE, Koeppe RA, Price JC, et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement. 2015;11:1‐15 e1‐4.
- Properzi MJ, Buckley RF, Chhatwal JP, et al. Nonlinear Distributional Mapping (NoDiM) for harmonization across amyloid‐PET radiotracers. Neuroimage. 2019;186:446‐454.
- Kim NK, Choi BH, Huang X, et al. Granulocyte‐macrophage colony‐stimulating factor promotes survival of dopaminergic neurons in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced murine Parkinson's disease model. Eur J Neurosci. 2009;29:891‐900.
- Mangano EN, Peters S, Litteljohn D, et al. Granulocyte macrophage‐colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease. Neurobiol Dis. 2011;43:99‐112.
- Kosloski LM, Kosmacek EA, Olson KE, Mosley RL, Gendelman HE. GM‐CSF induces neuroprotective and anti‐inflammatory responses in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine intoxicated mice. J Neuroimmunol. 2013;265:1‐10.
- Gendelman HE, Zhang Y, Santamaria P, et al. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double‐blind phase 1 clinical Parkinson's disease trial. NPJ Parkinsons Dis. 2017;3:10.
- Potter H, Wisniewski T. Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade. Int J Alzheimers Dis. 2012;2012:489428.
Source: PubMed