Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma

309

299

Significance This study demonstrates that antiangiogenic therapy increases tumor blood perfusion in a subset of newly diagnosed glioblastoma patients, and that it is these patients who survive longer when this expensive and potentially toxic therapy is combined with standard radiation and chemotherapy. This study provides fresh insights into the selection of glioblastoma patients most likely to benefit from antiangiogenic treatments.

Section: Discussionmentioning

confidence: 68%

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

Batchelor¹,

Gerstner²,

Emblem

et al. 2013

309

299

“…We previously have shown that anti-VEGF therapy can enhance the recruitment of TAMs in preclinical GBM models and that the number of TAMs is negatively correlated with survival in GBM patients, confirming their potential as a therapeutic target in GBM (11,68). A recent preclinical study in GBM found that survival could be enhanced by shifting the TAM phenotype away from an M2-like phenotype (33).…”

Section: Discussionmentioning

confidence: 84%

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Peterson

Kirkpatrick

Huang

et al. 2016

264

225

Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.

“…The two extremes of the phenotypic spectrum of TAMs are defined as the alternatively activated protumor (M2) versus classically activated antitumor (M1) states (23)(24)(25). We previously have shown that the degree of TAM infiltration in GBM patients treated with anti-VEGF therapy is inversely correlated with survival (26). These data point to the role of TAMs as potential mediators of resistance to anti-VEGF therapy in GBM.…”

Section: Significancementioning

confidence: 95%

Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival

Kloepper

Riedemann

Amoozgar

et al. 2016

300

245

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.