Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells

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Abstract

BACKGROUND Myeloid-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.METHODS A 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.RESULTS Eleven 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.CONCLUSIONS Low-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 REGISTRATION ClinicalTrials.gov NCT02669173.FUNDING This 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.

Authors

David M. Peereboom, Tyler J. Alban, Matthew M. Grabowski, Alvaro G. Alvarado, Balint Otvos, Defne Bayik, Gustavo Roversi, Mary McGraw, Pengjing Huang, Alireza M. Mohammadi, Harley I. Kornblum, Tomas Radivoyevitch, Manmeet S. Ahluwalia, Michael A. Vogelbaum, Justin D. Lathia