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Journal of Immunology (Baltimore, Md. :... Aug 2015G-CSF and GM-CSF are used widely to promote the production of granulocytes or APCs. The U.S. Food and Drug Administration approved G-CSF (filgrastim) for the treatment... (Review)
Review
G-CSF and GM-CSF are used widely to promote the production of granulocytes or APCs. The U.S. Food and Drug Administration approved G-CSF (filgrastim) for the treatment of congenital and acquired neutropenias and for mobilization of peripheral hematopoietic progenitor cells for stem cell transplantation. A polyethylene glycol-modified form of G-CSF is approved for the treatment of neutropenias. Clinically significant neutropenia, rendering an individual immunocompromised, occurs when their number is <1500/μl. Current guidelines recommend their use when the risk for febrile neutropenia is >20%. GM-CSF (sargramostim) is approved for neutropenia associated with stem cell transplantation. Because of its promotion of APC function, GM-CSF is being evaluated as an immunostimulatory adjuvant in a number of clinical trials. More than 20 million persons have benefited worldwide, and >$5 billion in sales occur annually in the United States.
Topics: Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neutropenia; Signal Transduction
PubMed: 26254266
DOI: 10.4049/jimmunol.1500861 -
Nature Communications Mar 2020Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and...
Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor resistance to oncolytic immunotherapy. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Genetic Engineering; Granulocyte-Macrophage Colony-Stimulating Factor; HEK293 Cells; Humans; Immunosuppression Therapy; Immunotherapy; Mice; Mice, Inbred C57BL; Oncolytic Virotherapy; Oncolytic Viruses; Recombinant Proteins
PubMed: 32170083
DOI: 10.1038/s41467-020-15229-5 -
Immunotherapy Aug 2021The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and... (Review)
Review
The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and immune-related adverse events persist as unmet needs. Sargramostim, a yeast-derived recombinant human GM-CSF, has shown clinical activity against diverse solid tumors, including metastatic melanoma. Here we review the use of sargramostim for treatment of advanced melanoma. Potential sargramostim applications in melanoma draw on the unique ability of GM-CSF to link innate and adaptive immune responses. We review preclinical and translational data describing the mechanism of action of sargramostim and synergy with immune checkpoint inhibitors to enhance efficacy and reduce treatment-related toxicity.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immune Checkpoint Inhibitors; Melanoma; Recombinant Proteins
PubMed: 34157863
DOI: 10.2217/imt-2021-0119 -
Journal of Clinical Oncology : Official... Mar 2023Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).
METHODS
Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.
RESULTS
SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.
CONCLUSION
SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.
Topics: Male; Humans; Female; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Temozolomide; Glioblastoma; Survivin; Antineoplastic Agents, Alkylating; Brain Neoplasms; Adjuvants, Immunologic; Vaccines, Subunit
PubMed: 36521103
DOI: 10.1200/JCO.22.00996 -
Alzheimer's & Dementia (New York, N. Y.) 2021Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation...
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 ( = .0074) and compared to placebo ( = .0370); the treatment effect persisted at FU1 ( = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% ( = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% ( = .0174) and 42% ( = .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.
PubMed: 33778150
DOI: 10.1002/trc2.12158 -
Frontiers in Pharmacology 2021This review summarizes the structure and function of the alveolar unit, comprised of alveolar macrophage and epithelial cell types that work in tandem to respond to... (Review)
Review
This review summarizes the structure and function of the alveolar unit, comprised of alveolar macrophage and epithelial cell types that work in tandem to respond to infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) helps to maintain the alveolar epithelium and pulmonary immune system under physiological conditions and plays a critical role in restoring homeostasis under pathologic conditions, including infection. Given the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and global spread of coronavirus disease 2019 (COVID-19), with subsequent acute respiratory distress syndrome, understanding basic lung physiology in infectious diseases is especially warranted. This review summarizes clinical and preclinical data for GM-CSF in respiratory infections, and the rationale for sargramostim (yeast-derived recombinant human [rhu] GM-CSF) as adjunctive treatment for COVID-19 and other pulmonary infectious diseases.
PubMed: 35111042
DOI: 10.3389/fphar.2021.735443 -
British Journal of Clinical Pharmacology Jul 2022Five patients, comprising nine treatment courses of sargramostim use in pulmonary alveolar proteinosis, are described. The prevailing standard of treatment, whole lung...
Five patients, comprising nine treatment courses of sargramostim use in pulmonary alveolar proteinosis, are described. The prevailing standard of treatment, whole lung lavage (WLL), is highly invasive, resource intensive and carries some procedural risk. Nebulised recombinant human GM-CSF (sargramostim) offers a pharmacological treatment option, allowing patients to be treated at home, possessing potential advantages in patient experience and wider health resourcing. The majority of reported patients described subjective improvement in symptoms along with radiographical improvement, although this did not translate into significant improvement in pulmonary function testing. Drug scarcity and high drug cost remain potential barriers to accessing this treatment, and so careful patient selection and treatment outcome assessment remain as challenging needs. Incorporating the routine assessment of validated patient symptom scores with objective physiological measures will allow prediction of response to treatment and help guide management. This report describes the largest published experience of sargramostim use in Australia.
Topics: Australia; Bronchoalveolar Lavage; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Pulmonary Alveolar Proteinosis; Recombinant Proteins
PubMed: 35156221
DOI: 10.1111/bcp.15266