Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease

Abstract

Background: Neuroinflammation plays a pathogenic role in Parkinson's disease (PD). Immunotherapies that restore brain homeostasis can mitigate neurodegeneration by transforming T cell phenotypes. Sargramostim has gained considerable attention as an immune transformer through laboratory bench to bedside clinical studies. However, its therapeutic use has been offset by dose-dependent adverse events. Therefore, we performed a reduced drug dose regimen to evaluate safety and to uncover novel disease-linked biomarkers during 5 days/week sargramostim treatments for one year. Methods: Five PD subjects were enrolled in a Phase 1b, unblinded, open-label study to assess safety and tolerability of 3 mg/kg/day sargramostim. Complete blood counts and chemistry profiles, physical examinations, adverse events (AEs), immune profiling, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, T cell phenotypes/function, DNA methylation, and gene and protein patterns were evaluated.Findings: Sargramostim administered at 3 mg/kg/day significantly reduced numbers and severity of AEs/subject/month compared to 6 mg/kg/day treatment. While MDS-UPDRS Part III score reductions were recorded, peripheral blood immunoregulatory phenotypes and function were elevated. Hypomethylation of upstream FOXP3 DNA elements was also increased.Interpretation: Long-term sargramostim treatment at 3 mg/kg/day is well-tolerated and effective in restoring immune homeostasis. There were decreased numbers and severity of AEs and restored peripheral immune function coordinate with increased numbers and function of Treg. MDS-UPDRS Part III scores did not worsen. Larger patient numbers need be evaluated to assess conclusive drug efficacy (ClinicalTrials.gov NCT03790670). Funding: The research was supported by community funds to the University of Nebraska Foundation and federal research support from 5 R01NS034239-25.

Monocyte biomarkers define sargramostim treatment outcomes for Parkinson's disease

“…The study was an unblinded, open‐label, single‐centre phase 1 clinical trial performed at the University of Nebraska Medical Center (UNMC), Omaha, NE, USA. 14 All patients were recruited from the Omaha metropolitan area and treated for 12 months between January, 2019 and July, 2020. The study was designed to test safety, tolerability, and biomarker discovery of sargramostim regimen of 3 µg/kg/day (5 days on and 2 days off).…”

“… 14 Exclusion criteria included inability to undergo leukapheresis, poor venous access, use of a wheelchair, walker, and/or cane, corticobasal degeneration, multiple system atrophy, unilateral Parkinsonism of >3 years, prior head injury, stroke, brain surgery including deep brain stimulation, a family history of >1 blood relative with PD, mental illness, cognitive impairment, autoimmune, systemic inflammatory or hematologic diseases, past treatment with sargramostim, current treatment with neuroleptics or lithium, past immunosuppressive treatments, and known allergies to colony‐stimulating factors (CSFs) or yeast‐derived products. 14 PD patients underwent three pre‐treatment monthly interval appointments to determine baseline immune, hematologic, and metabolic profiles. 14 On the third visit, subjects self‐administered sargramostim at 3 µg/kg/day (5 days on and 2 days off) subcutaneously for 12 months; returning for clinical assessments every 4 weeks.…”

“… 14 PD patients underwent three pre‐treatment monthly interval appointments to determine baseline immune, hematologic, and metabolic profiles. 14 On the third visit, subjects self‐administered sargramostim at 3 µg/kg/day (5 days on and 2 days off) subcutaneously for 12 months; returning for clinical assessments every 4 weeks. The primary neurologist performed all Unified Parkinson's Disease Rating Scale (UPDRS) assessments during each appointment.…”

“… 10 , 11 Restoration of Treg numbers and function by immune modulatory agents leads to control of neuroinflammation and neuroprotection. 12 This was demonstrated for granulocyte‐macrophage colony‐stimulating factor (GM‐CSF, sargramostim, Leukine ® ), 13 , 14 , 15 , 16 vasoactive intestinal peptide (VIP), 17 and by ex vivo immune transformation. 18 Moreover, pre‐clinical and clinical studies of immune modulatory therapies have shown benefits for PD, AD, ALS, and stroke as well as multiple sclerosis (MS) and rheumatoid arthritis (RA), 13 , 14 , 15 , 16 , 19 , 20 , 21 and raises the possibility that neuroprotective therapies can supplement symptomatic disease control.…”

“…To evaluate innate responses in immune modulatory therapy in PD, we evaluated the transcriptional and translational changes of monocytes during sargramostim treatment of PD subjects. 14 The studies seek a cogent explanation for linkages between innate immune activation, inflammation, and adaptive Teff to Treg transformation for disease. We posit that uncovering such monocyte‐linked neuroprotective mechanisms provides predictive and/or monitoring biomarkers for therapeutic responses and possibly disease progression.…”