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

Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh; Seano, Giorgio; Susek, Katharina Helene; Yu, Veronica; Dalvie, Nisha; Amelung, Robin L.; Datta, Meenal; Song, Jonathan W.; Askoxylakis, Vasileios; Taylor, Jennie; Lu-Emerson, Christine; Batista, Ana; Kirkpatrick, Nathaniel D.; Jung, Keehoon; Snuderl, Matija; Muzikansky, Alona; Stubenrauch, Kay; Krieter, Oliver; Wakimoto, Hiroaki; Xu, Lei; Munn, Lance L.; Duda, Dan G.; Fukumura, Dai; Batchelor, Tracy T.; Jain, Rakesh K.

doi:10.1073/pnas.1525360113

Cited by 279 publications

(233 citation statements)

References 68 publications

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“…5E), suggesting that dual therapy may shift the balance of TAMs toward an antitumor phenotype. This observation is further supported by data in our companion paper showing that simultaneous blockade of Ang-2 and VEGF using a bispecific antibody significantly induces M1-like TAM polarization and increases the M1/M2 ratio compared with VEGF-inhibition alone in vivo (61).…”

Section: Discussionsupporting

confidence: 71%

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

Proc. Natl. Acad. Sci. U.S.A.

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248

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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.

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Section: Discussionsupporting

confidence: 71%

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

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

248

210

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“…In this context, the strong upregulation of Ang2 in the tumor endothelium (46,47) and its destabilizing effect on tumor vasculature (48) have made this cytokine a very attractive therapeutic target. Its inhibition in association with VEGF therapy normalizes tumor vasculature and has shown pronounced effects on overall survival in preclinical tumor models (49,50). Yet, these preclinical findings have not yet translated into an improved therapeutic effect of VEGF/ angiogenesis and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

Porta¹,

Roth²,

Singhal³

et al. 2018

Journal of Clinical Investigation

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“…Experimental data indicate that VEGF and ANG2 might cooperate to induce tumour immunosuppression and that this effect might be dependent on the relative levels of these cytokines in the TME 35–37 . Importantly, however, preclinical evidence indicates that high-dose and/or long-term antiangiogenic therapy causes massive vessel pruning and increases immunosuppression in tumour models 37–40 , suggesting that an optimum level of VEGF and ANG2 blockade will be needed to alleviate immunosuppression in the TME.…”

Section: The Abnormal Tumour Vasculaturementioning

confidence: 99%

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

et al. 2018

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Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.

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

Cited by 279 publications

References 68 publications

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

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

Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

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