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Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma.Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients.Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1+ monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9.Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis. Clin Cancer Res; 17(14); 4872–81. ©2011 AACR.

Supplementary Figure 1 from Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept

Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma. Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients. Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1+ monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9. Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis. Clin Cancer Res; 17(14); 4872–81. ©2011 AACR.

BACKGROUND: (blind field). METHODS: Patients with recurrent high grade gliomas were enrolled in one of two arms. Group A patients (clinical assessment group) received a single intratumoral injection of DNX-2401 into biopsy-proven recurrent glioma. Group B patients (biological endpoint group) received an initial intratumoral injection through a permanently implanted catheter (to identify the injection site) followed 14 days later by en bloc tumor resection (to obtain post-treatment specimens) and subsequent injection of DNX-2401 into the post-resection tumor bed. Dose was escalated from 1x10^7 to 3x10^10 viral particles (vp) in 8 cohorts. Patients were followed with clinical exams, MRIs, and laboratory studies. RESULTS: Histological analysis of post-treatment en bloc surgical specimens cut perpendicular to the implanted catheter proved for the first time that DNX-2401 was capable of infecting, replicating in, and killing human glioma tumor cells (Group B; N = 12). The maximum dose achieved was 3 × 10^10 vp as planned (Group A; N = 25). DNX-2401 resulted in no toxicity in each cohort. Ongoing outcome analyses show an overall median survival of 11 months. Remarkably, complete responses were seen in 3 patients (12%) (#12, #33, #37), all of whom are currently alive with no evidence of disease (3.2, 2 and 1.75 years after treatment). Serial MRIs revealed a period of increased enhancement prior to tumor regression, consistent with an inflammatory response. Histological analysis of a resected tumor from a symptomatic patient (#20) in Arm A during this period of increased MRI-enhancement identified primarily inflammatory cells (macrophages/CD8 T-cells) and only rare glioma cells. Analyses of inflammatory cytokines in serum revealed that, compared with all other patients, the 3 responders had 10-fold to 10,000-fold increases in Interleukin-12p70 (which polarizes T(h)0-cells to T(h)1-cells and promotes cell-mediated immunity). CONCLUSIONS: DNX-2401 is a new oncolytic virus with a favorable toxicity profile that is capable of replicating in and killing human glioma cells. Efficacy in this early stage trial was impressive with a 12% complete response-rate that has proven to be durable. Molecular studies suggest that viral-induced, anti-tumor cytotoxic immunity (in situ vaccine) may play a role in the anti-glioma effect of DNX-2401. SECONDARY CATEGORY: Immunobiology & Immunotherapy.