Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.
نویسندگان
چکیده
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.
منابع مشابه
P157: Periostin Recruits Tumor Associated Macrophages in Glioblastoma Multiform
Glioblastoma multiform (GBM) is the most common and lethal type of primary brain tumors with high rates of morbidity and mortality. Treatment options are limited and ineffective in most of the cases. Epidemiological studies have shown a link between inflammation and glioma genesis. In addition, at the molecular level, pro-inflammatory cytokines released from activated microglia can increa...
متن کاملAnti-tumoral, anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2
Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody...
متن کاملO27: Interaction of Cancer Stem Cells and Microglia in Glioblastoma Multiforme
Malignant gliomas are highly invasive brain tumors with the occurrence of multiple microglia/macrophages in the tumor microenvironment. Macrophages/microglia that found in glioma microenvironment, as tumor-infiltrating immune cells, can play a harmful role in tumor progression. In addition, glioblastoma multiforme (GBM) contains multiple aberrant differentiation and tumorigenic cancer stem cell...
متن کاملTargeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival
Glioblastoma (GBM) is the most malignant brain tumor where patients' survival is only 14.6 months, despite multimodal therapy with debulking surgery, concurrent chemotherapy and radiotherapy. There is an urgent, unmet need for novel, effective therapeutic strategies for this devastating disease. Although several immunotherapies are under development for the treatment of GBM patients, the use of...
متن کاملP10: Isolation and Culture of Primary Microglial Cells from Glioblastoma Patients
Glioblastoma multiform (GBM) is the most common and malignant form of glial tumors. GBM microenvironment contains various cell types showing characteristics of activated or dimorphic macrophages/microglia. Some of these cells provide significant help for tumor growth, while others are able to inhibit tumor progression. Microglia play a major role in brain function by monitoring tissue for patho...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 113 16 شماره
صفحات -
تاریخ انتشار 2016