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

Abstract

Background: Myeloid-derived suppressor cells (MDSCs) are elevated in glioblastoma (GBM) patient circulation, 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 0/1 dose-escalation clinical trial was conducted in recurrent glioblastoma patients treated 5-7 days prior to 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 multi-parameter flow cytometry, and tumor tissue immune profiles were assessed via mass cytometry time-of-flight.Results: A total of 11 patients were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid, with a progression-free survival of 5.8 months (range of 1.8-27.8 months) and an overall survival of 11.5 months (range of 3->28.0 months) from trial enrollment. No serious adverse events related to the drug combination were observed. Compared to pre-treatment 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 to untreated GBM patients in the 300 mg and 450 mg treatment arms. Conclusions:Low-dose, metronomic capecitabine in combination with bevacizumab is 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.

Immunological impact of chemotherapy on the tumor microenvironment in gastric cancer

“…The TME can be modulated by chemotherapy. [22][23][24] This study revealed that chemotherapy can induce significant changes in the immune background within the TME (i.e., increases in T cell markers…”

Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner

“…In contrast, nucleoside analogs were shown to reduce MDSC frequencies in various tumor types via a mechanism that was not well defined (25)(26)(27)(28). Our studies in mouse models and patients with GBM, indicated that 5-fluorouracil (5-FU) and its oral formulation capecitabine could be promising candidates to target innate immunosuppression (29,30), of which fludarabine was predicted to be more effective (Supplementary Fig. 6E).…”

Myeloid Cells in Glioblastoma Microenvironment

“…The depletion of circulating MDSCs using 5-flurouracil (5-FU) resulted in increased frequencies of activated T cells and prolonged survival in pre-clinical models [ 112 ]. In patients undergoing surgery for recurrent GBM, the depletion of MDSCs using metronomic capecitabine increased cytotoxic immune infiltration in brain tumors [ 113 ]. Another study showed that TMZ chemotherapy may also be used to deplete MDSC.…”