Phase 2 and biomarker study of trebananib, an angiopoietin‐blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma

Reardon, David A.; Lassman, Andrew B.; Schiff, David; Yunus, Shakeeb; Gerstner, Elizabeth R.; Cloughesy, Timothy F.; Lee, Eudocia Quant; Gaffey, Sarah; Barrs, Jennifer; Bruno, Jennifer; Muzikansky, Alona; Duda, D.; Jain, Rakesh K.; Wen, Patrick Y.

doi:10.1002/cncr.31172

Cited by 41 publications

(35 citation statements)

References 46 publications

(116 reference statements)

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“…One possible reason for the clinical failure of dual ANG1–ANG2 blockade is that inhibition of ANG1, which is an agonistic ligand of TIE2 (BOX 3), might compromise the benefits of vascular normalization conferred by the blockade of the antagonistic TIE2 ligand ANG2 (REF. 88). Importantly, clinical trials of ANG2-specific inhibitors are currently ongoing (Supplementary Table S8).…”

Section: Strategies To Normalize Tumour Vesselsmentioning

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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Section: Strategies To Normalize Tumour Vesselsmentioning

confidence: 99%

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

et al. 2018

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“…Molecules in EC-SMC interactions have been recognized as therapeutic targets, inhibiting angiogenesis in tumor microenvironments [50,51]. For example, Trebananib, an Ang-1/-2 neutralizing petibody, inhibits Ang-1/Tie-2 interactions [52,53]. Receptor tyrosine kinase inhibitors, such as Cediranib, Nintedanib and Sorafenib inhibit signaling pathways of VEGFRs and PDGFRs [54].…”

Section: Discussionmentioning

confidence: 99%

An organotypicin vitromodel of matured blood vessels

Lee

2020

Preprint

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Angiogenesis is a physiological process in which brand-new blood vessels are formed from pre-existing blood vessels. The angiogenic processes are achieved by multiple steps, including angiogenic vascular sprouting, lumen formation, mural cell (e.g., smooth muscle cells) recruitment, and vessel stabilization by the mural cell coverage of the neovessels. Especially, mural cell recruitment to and coverage of the newly formed endothelium is a fundamental process to provide fully matured, functional blood vessels. Although investigation of the mural cell interactions with endothelial cells is crucial not only for better understanding of vascular physiology, but also for treating numerous vascular diseases, there has been a lack of three-dimensional (3D) in vitro models that recapitulate spontaneous processes of the vascular maturation. In this study, we describe an organotypic in vitro model that represents multi-step, spontaneous vascular maturation processes, which includes angiogenic vessel sprouting, smooth muscle cell (SMC) recruitment, and the SMC coverage of the neovessels. Using the system, we could spatiotemporally control vessel sprouting and vessel stabilization/maturation; and revealed an optimal condition that could reconstitute SMC-covered, matured blood vessels in 3D in vitro. We may provide a new platform for future mechanism studies of vascular interactions to mural cells and vessel maturation; and for pre-clinical screening and validation of therapeutic agent candidates for treating vascular diseases.

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“…However, no improvement was observed in patients with GB treated with these factors in clinical trials. [25][26][27] effects of antiangiogenic factors on the tumor vasculature…”

Section: Antiangiogenic Tyrosine Kinase Inhibitors (Tkis)mentioning

confidence: 99%

<p>Nanocarriers and nonviral methods for delivering antiangiogenic factors for glioblastoma therapy: the story so far</p>

Clavreul¹,

Pourbaghi-Masouleh²,

Roger³

et al. 2019

IJN

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Angiogenesis, the formation of new blood vessels, is an essential component of glioblastoma (GB) progression. The development of angiogenesis inhibitor therapy, including treatments targeting vascular endothelial growth factor (VEGF) in particular, raised new hopes for the treatment of GB, but no Phase III clinical trial to date has reported survival benefits relative to standard treatment. There are several possible reasons for this limited efficacy, including VEGF-independent angiogenesis, induction of tumor invasion, and inefficient antiangiogenic factor delivery to the tumor. Efforts have been made to overcome these limitations by identifying new angiogenesis inhibitors that target angiogenesis through different mechanisms of action without inducing tumor invasion, and through the development of viral and nonviral delivery methods to improve antiangiogenic activity. Herein, we describe the nonviral methods, including convection-enhanced delivery devices, implantable polymer devices, nanocarriers, and cellular vehicles, to deliver antiangiogenic factors. We focus on those evaluated in intracranial (orthotopic) animal models of GB, the most relevant models of this disease, as they reproduce the clinical scenario of tumor progression and therapy response encountered in GB patients.

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Phase 2 and biomarker study of trebananib, an angiopoietin‐blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma

Abstract: Angiopoietin 1 and angiopoietin 2 inhibition with trebananib was ineffective as monotherapy and did not enhance the ability of VEGF blockade with bevacizumab to improve the outcomes of patients with recurrent glioblastoma. Cancer 2018;124:1438-48. © 2017 American Cancer Society.

Cited by 41 publications

References 46 publications

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

An organotypicin vitromodel of matured blood vessels

<p>Nanocarriers and nonviral methods for delivering antiangiogenic factors for glioblastoma therapy: the story so far</p>

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