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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 preexisting 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 also 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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Acknowledgements

We would like to thank Nisha Gupta, Echoe Bouta and Patrycja Nowak-Sliwinka for helpful comments and Lance L. Munn for providing the illustration. We apologize to authors whose original work we could not cite due to limitations on the number of references.

Funding

RRR received funding from Dutch Cancer Society (KWF), Stichting Nijbakker-Morra, Stichting Bekker-La-Bastide Fonds, Dittmer Fonds, VU Fondsendesk. DGD’s work was supported through NIH Grants P01-CA080124, R01-CA159258, R21-CA139168 and Proton Beam/Federal Share Program, and the American Cancer Society Grant 120733-RSG-11-073-01-TBG.

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Authors and Affiliations

  1. E. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom St, Cox-734, Boston, MA, 02114, USA

    Rakesh R. Ramjiawan & Dan G. Duda

  2. Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    Rakesh R. Ramjiawan & Arjan W. Griffioen

Authors
  1. Rakesh R. Ramjiawan
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  2. Arjan W. Griffioen
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  3. Dan G. Duda
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Corresponding author

Correspondence to Dan G. Duda.

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Conflict of interest

DGD receives research funding from Merrimack, Leap Tx, Bristol-Myers Squibb and Bayer.

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Ramjiawan, R.R., Griffioen, A.W. & Duda, D.G. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?. Angiogenesis 20, 185–204 (2017). https://doi.org/10.1007/s10456-017-9552-y

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  • DOI: https://doi.org/10.1007/s10456-017-9552-y

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