Work

Actr-09. Targeting Myeloid Derived Suppressor Cells: Phase 0/1 Trial of Low Dose Capecitabine + Bevacizumab in Patients With Recurrent Glioblastoma

Year: 2018

Type: article

Abstract: Glioblastoma (GBM) creates an immunosuppressive environment that allows tumor growth. Myeloid derived suppressor cells (MDSCs) mediate immunosuppression in GBMs. MDSCs are up-regulated in the blood of GBM patients. We have developed a novel strategy to target GBM immunosuppression using low dose 5-fluorouracil (5-FU) to target MDSCs. Marked MDSC depletion occurs at 5-FU doses in mice equivalent to <10% of the normal human dosing. Goal: proof of concept that MDSC suppression is feasible in GBM patients with low-dose capecitabine [cap], (oral 5-FU analogue). Eligibility: Recurrent GBM in need of surgical resection; no prior cap or bevacizumab. Cohorts of 3–6 patients receive low-dose cap 150 mg/m2/d (dose level 1) for 7 days pre-surgery. Post-op, patients resume cap for one cycle after which bev is added. Concentrations of blood MDSCs, immune cells, and relevant secreted factors are measured at baseline; pre- and post-op; and after the addition of bev. Tumors are assayed for MDSCs and glioma stem-like cells (GSCs). Primary endpoint: MDSC and T-regulatory cell (T-reg) reduction after cap. Seven patients have enrolled to date. In all patients MDSCs rose initially after resection (max rise 18% over baseline) and subsequently began to fall after cycle 2 (max reduction 6%). T-regs fell slightly (0–12%) in 5 of 7 patients. Cytotoxic T-cell (CTL) concentrations rose significantly (max 93%). CD3+ T-cells fell in 5 of 7 patients (max reduction 52%). Four of 7 (71%) of patients reached PFS6. Median PFS-6 months (2–14 mos). Median overall survival 10 months (5–16). Treatment-related SAEs: grade 3 dyspnea; grade 2 hemorrhage, non-neutropenic fever; and grade 1 hand-foot. Low-dose capecitabine is associated with a modest reduction in MDSCs and T-regs and a significant increase in CTLs. Toxicity has been manageable. Four of 7 evaluable patients have reached 6 months free of progression. Dose escalation continues.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noy148.044