Anti-angiogenic Agents - Overcoming Tumour Endothelial Cell Anergy and Improving Immunotherapy Outcomes

Overview

Journal Nat Rev Clin Oncol

Specialty Oncology

Date 2021 Apr 9

PMID 33833434

Citations 149

Authors

Zowi R Huinen

Elisabeth J M Huijbers

Judy R van Beijnum

Patrycja Nowak-Sliwinska

Arjan W Griffioen

Affiliations

Soon will be listed here.

Abstract

Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. A compelling body of evidence indicates that anti-angiogenic therapy has the capacity to ameliorate antitumour immunity owing to the inhibition of various immunosuppressive features of angiogenesis. Hence, combinations of anti-angiogenic agents and immunotherapy are currently being tested in >90 clinical trials and 5 such combinations have been approved by the FDA in the past few years. In this Perspective, we describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as the vascular counterpart of immune checkpoints. We review the antitumour immunity-promoting effects of anti-angiogenic agents and provide an update on the current clinical successes achieved when these agents are combined with immune checkpoint inhibitors. Finally, we propose that anti-angiogenic agents are immunotherapies - and vice versa - and discuss future research priorities.

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References

Hodi F, ODay S, Mcdermott D, Weber R, Sosman J, Haanen J . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711-23. PMC: 3549297. DOI: 10.1056/NEJMoa1003466. View

Wolchok J, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J, Cowey C . Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017; 377(14):1345-1356. PMC: 5706778. DOI: 10.1056/NEJMoa1709684. View

Borghaei H, Paz-Ares L, Horn L, Spigel D, Steins M, Ready N . Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015; 373(17):1627-39. PMC: 5705936. DOI: 10.1056/NEJMoa1507643. View

Motzer R, Escudier B, Mcdermott D, George S, Hammers H, Srinivas S . Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015; 373(19):1803-13. PMC: 5719487. DOI: 10.1056/NEJMoa1510665. View

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob J, Cowey C, Lao C . Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015; 373(1):23-34. PMC: 5698905. DOI: 10.1056/NEJMoa1504030. View

Dong H, Strome S, Salomao D, Tamura H, Hirano F, Flies D . Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8(8):793-800. DOI: 10.1038/nm730. View

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Topalian S, Taube J, Anders R, Pardoll D . Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016; 16(5):275-87. PMC: 5381938. DOI: 10.1038/nrc.2016.36. View

Chen D, Mellman I . Elements of cancer immunity and the cancer-immune set point. Nature. 2017; 541(7637):321-330. DOI: 10.1038/nature21349. View

10.

Robert C, Long G, Brady B, Dutriaux C, Maio M, Mortier L . Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2014; 372(4):320-30. DOI: 10.1056/NEJMoa1412082. View

11.

Brahmer J, Reckamp K, Baas P, Crino L, Eberhardt W, Poddubskaya E . Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015; 373(2):123-35. PMC: 4681400. DOI: 10.1056/NEJMoa1504627. View

12.

Wolchok J, Kluger H, Callahan M, Postow M, Rizvi N, Lesokhin A . Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013; 369(2):122-33. PMC: 5698004. DOI: 10.1056/NEJMoa1302369. View

13.

ODonnell J, Teng M, Smyth M . Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol. 2018; 16(3):151-167. DOI: 10.1038/s41571-018-0142-8. View

14.

Sharma P, Allison J . The future of immune checkpoint therapy. Science. 2015; 348(6230):56-61. DOI: 10.1126/science.aaa8172. View

15.

Vanneman M, Dranoff G . Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012; 12(4):237-51. PMC: 3967236. DOI: 10.1038/nrc3237. View

16.

Griffioen A, Molema G . Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev. 2000; 52(2):237-68. View

17.

Rahma O, Hodi F . The Intersection between Tumor Angiogenesis and Immune Suppression. Clin Cancer Res. 2019; 25(18):5449-5457. DOI: 10.1158/1078-0432.CCR-18-1543. View

18.

Motz G, Coukos G . The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol. 2011; 11(10):702-11. DOI: 10.1038/nri3064. View

19.

Hicklin D, Ellis L . Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2004; 23(5):1011-27. DOI: 10.1200/JCO.2005.06.081. View

20.

Gabrilovich D, Chen H, Girgis K, Cunningham H, Meny G, Nadaf S . Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996; 2(10):1096-103. DOI: 10.1038/nm1096-1096. View