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      Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

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          Abstract

          Angiogenesis is defined as the formation of new blood vessels from pre-existing vessels, and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients, and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time-window. However, anti-angiogenics may excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.

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          Author and article information

          Journal
          9814575
          22063
          Angiogenesis
          Angiogenesis
          Angiogenesis
          0969-6970
          1573-7209
          1 April 2017
          30 March 2017
          May 2017
          01 May 2018
          : 20
          : 2
          : 185-204
          Affiliations
          [1 ]E. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
          [2 ]Angiogenesis Laboratory, Cancer Center Amsterdam, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
          Author notes
          [* ] Corresponding author: Dan G. Duda, DMD, PhD, 100 Blossom St, Cox-734, Boston, MA 02114, USA. Tel: 1-617-726-4648; Fax 1-617-7261962; gduda@ 123456partners.org
          Article
          PMC5439974 PMC5439974 5439974 nihpa864322
          10.1007/s10456-017-9552-y
          5439974
          28361267
          a1aed6c4-b3f3-4e25-9ec6-ee988f424298
          History
          Categories
          Article

          vascular normalization,hypoxia,VEGF,immunotherapy,Anti-angiogenesis,immunosuppression

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