Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells
Year: 2019
Type: article
Study design: Clinical Trial
Abstract: BACKGROUNDMyeloid-derived suppressor cells (MDSCs) are elevated in the circulation of patients with glioblastoma (GBM), present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated.METHODSA phase 0/I dose-escalation clinical trial was conducted in patients with recurrent GBM treated 5-7 days before surgery with low-dose chemotherapy via capecitabine, followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multiparameter flow cytometry, and tumor tissue immune profiles were assessed via time-of-flight mass cytometry.RESULTSEleven patients total were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid. No serious adverse events related to the drug combination were observed. Compared with pretreatment baseline, circulating MDSCs were found to be higher after surgery in the 150-mg treatment arm and lower in the 300-mg and 450-mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared with untreated GBM patients in the 300-mg and 450-mg treatment arms.CONCLUSIONSLow-dose, metronomic capecitabine in combination with bevacizumab was well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment.TRIAL REGISTRATIONClinicalTrials.gov NCT02669173.FUNDINGThis research was funded by the Cleveland Clinic, Case Comprehensive Cancer Center, the Musella Foundation, B*CURED, the NIH, the National Cancer Institute, the Sontag Foundation, Blast GBM, the James B. Pendleton Charitable Trust, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Capecitabine was provided in kind by Mylan Pharmaceuticals.
Source: JCI Insight
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Musella Foundation For Brain Tumor Research and Information, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Sontag Foundation, Cleveland Clinic, Case Comprehensive Cancer Center, Case Western Reserve University, James B. Pendleton Charitable Trust, Mylan, National Institutes of Health, Center for AIDS Research, University of Washington, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, Jonsson Comprehensive Cancer Center
Awards: G1100959374, G1685810784, G180317997, G2614396188, The immunosuppressive role of glioblastoma-derived macrophage migration inhibitor factor, G6112660351, UCLA Center for AIDS Research (CFAR), G9000014846, G9000261587, G9000271699, UCLA SPORE in Brain Cancer, Cancer Center Support Grant, Cancer Biology Training Grant
OpenAlex ID: W2979472290