Skip to main content

Advertisement

SpringerLink
Log in

Immune Effects of Bevacizumab: Killing Two Birds with One Stone

  • Review Paper
  • Published:
Cancer Microenvironment

Abstract

Angiogenesis or new vessel formation is essential for tumour growth and progression. Therefore, targeting angiogenesis has been an attractive strategy in the treatment ofcancer. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody thattargets vascular endothelial growth factor-A (VEGF-A) - a key molecular player inangiogenesis. Bevacizumumab has shown clinical efficacy in phase III clinical trials inseveral advanced solid malignancies. The clinical efficacy of bevacizumumab isprimarily due to its antiangiogenic effects; however, there are direct antitumor effectsand immunomodulatory effects. Enhancing the immune system to restore itsantitumour activity has been utilized successfully in clinical setting. In this article we willdiscuss the possible immunomodulatory effects of the most clinically usedantiangiogenic agent; bevacizumumab.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Shih T, Lindley C (2006) Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 11:1779–802

    Article  Google Scholar 

  2. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27(8):1227–34

    Article  CAS  PubMed  Google Scholar 

  3. Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH (2008) Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non-small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol 26(1):60–5

    Article  CAS  PubMed  Google Scholar 

  4. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–9

    Article  CAS  PubMed  Google Scholar 

  5. Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D, First BEAT (2009) investigators. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 20(11):1842–7

    Article  PubMed  Google Scholar 

  6. Valachis A, Polyzos NP, Patsopoulos NA, Georgoulias V, Mavroudis D, Mauri D (2010) Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat 122(1):1–7

    Article  CAS  PubMed  Google Scholar 

  7. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–76

    Article  CAS  PubMed  Google Scholar 

  8. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O’Shaughnessy J (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–60

    Article  CAS  PubMed  Google Scholar 

  9. Escudier B, Szczylik C, Porta C, Gore M (2012) Treatment selection in metastatic renal cell carcinoma: expert consensus. Nat Rev Clin Oncol 9(6):327–37

    Article  CAS  PubMed  Google Scholar 

  10. Escudier B, Albiges L (2011) Vascular endothelial growth factor-targeted therapy for the treatment of renal cell carcinoma. Drugs 71(9):1179–91

    Article  CAS  PubMed  Google Scholar 

  11. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR (2012) OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 30(17):2039–45

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stähle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM (2011) ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484–96

    Article  CAS  PubMed  Google Scholar 

  13. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX (2011) Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365(26):2473–83

    Article  CAS  PubMed  Google Scholar 

  14. Tewari KS1, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ (2014) Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 20;370(8):734–43

    Article  Google Scholar 

  15. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–91

    Article  CAS  PubMed  Google Scholar 

  17. Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D, Hewitt SM, Berman A, Steinberg SM, Liewehr DJ, Plehn J, Doshi A, Thomasson D, McCarthy N, Koeppen H, Sherman M, Zujewski J, Camphausen K, Chen H, Swain SM (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24(5):769–77

    Article  CAS  PubMed  Google Scholar 

  18. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–74

    Article  CAS  PubMed  Google Scholar 

  19. Mlecnik B, Bindea G, Pagès F, Galon J (2011) Tumor immunosurveillance in human cancers. Cancer Metastasis Rev 30(1):5–12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21(3):309–22

    Article  CAS  PubMed  Google Scholar 

  21. Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316(8):1324–31

    Article  CAS  PubMed  Google Scholar 

  22. Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12(4):265–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Yang DH, Park JS, Jin CJ, Kang HK, Nam JH, Rhee JH, Kim YK, Chung SY, Choi SJ, Kim HJ, Chung IJ, Lee JJ (2009) The dysfunction and abnormal signaling pathway of dendritic cells loaded by tumor antigen can be overcome by neutralizing VEGF in multiple myeloma. Leuk Res 33(5):665–70

    Article  CAS  PubMed  Google Scholar 

  24. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92(11):4150–66

    CAS  PubMed  Google Scholar 

  25. Young MR, Kolesiak K, Wright MA, Gabrilovich DI (1999) Chemoattraction of femoral CD34+ progenitor cells by tumor-derived vascular endothelial cell growth factor. Clin Exp Metastasis 17(10):881–8

    Article  CAS  PubMed  Google Scholar 

  26. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI (1998) Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 160(3):1224–32

    CAS  PubMed  Google Scholar 

  27. Young MR, Kolesiak K, Wright MA, Gabrilovich DI (1999) Chemoattraction of femoral CD34+ progenitor cells by tumor-derived vascular endothelial cell growth factor. Clin Exp Metastasis 17(10):881–8

    Article  CAS  PubMed  Google Scholar 

  28. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187(3):1579–86

    Article  CAS  PubMed  Google Scholar 

  29. Ziegler BL, Valtieri M, Porada GA, De Maria R, Müller R, Masella B, Gabbianelli M, Casella I, Pelosi E, Bock T, Zanjani ED, Peschle C. KDR receptor: a key marker defining hematopoietic stem cells. Sci 199;285(5433):1553–8

  30. Dikov MM, Ohm JE, Ray N, Tchekneva EE, Burlison J, Moghanaki D, Nadaf S, Carbone DP (2005) Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 174(1):215–22

    Article  CAS  PubMed  Google Scholar 

  31. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2(10):1096–103

    Article  CAS  PubMed  Google Scholar 

  32. Mimura K, Kono K, Takahashi A, Kawaguchi Y, Fujii H (2007) Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2. Cancer Immunol Immunother 56(6):761–70

    Article  CAS  PubMed  Google Scholar 

  33. Laxmanan S, Robertson SW, Wang E, Lau JS, Briscoe DM, Mukhopadhyay D (2005) Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways. Biochem Biophys Res Commun 334(1):193–8

    Article  CAS  PubMed  Google Scholar 

  34. Ohm JE, Gabrilovich DI, Sempowski GD, Kisseleva E, Parman KS, Nadaf S, Carbone DP (2003) VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101(12):4878–86

    Article  CAS  PubMed  Google Scholar 

  35. Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Ioannou K, Ziogas AC, Rodolakis A, Vlahos G, Thomakos N, Haidopoulos D, Terpos E, Antsaklis A, Dimopoulos MA, Bamias A (2012) VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br J Cancer 107(11):1869–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Basu A, Hoerning A, Datta D, Edelbauer M, Stack MP, Calzadilla K, Pal S, Briscoe DM (2010) Cutting edge: vascular endothelial growth factor-mediated signaling in human CD45RO + CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma production. J Immunol 184(2):545–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Zhang J, Silva T, Yarovinsky T, Manes TD, Tavakoli S, Nie L, Tellides G, Pober JS, Bender JR, Sadeghi MM (2010) VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodelling. Circ Res 107(3):408–17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124(1):175–89

    Article  CAS  PubMed  Google Scholar 

  39. Burrell K, Singh S1, Jalali S1, Hill RP2, Zadeh G (2014) VEGF regulates region-specific localization of perivascular bone marrow-derived cells in glioblastoma. Cancer Res 74(14):3727–39

    Article  CAS  PubMed  Google Scholar 

  40. Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K, Morisaki T, Katano M (2010) VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol 40(1):197–203

    Article  CAS  PubMed  Google Scholar 

  41. Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G (2014) Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumours. Nat Med 20(6):607–15

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Radisavljevic Z, Avraham H, Avraham S (2000) Vascular endothelial growth factor up-regulates ICAM-1 expression via the phosphatidylinositol 3 OH-kinase/AKT/Nitric oxide pathway and modulates migration of brain microvascular endothelial cells. J Biol Chem 275:20770–20774

    Article  CAS  PubMed  Google Scholar 

  43. Lee TH, Avraham H, Lee SH, Avraham S (2002) Vascular endothelial growth factor modulates neutrophil transendothelial migration via up-regulation of interleukin-8 in human brain microvascular endothelial cells. J Biol Chem 277(12):10445–51

    Article  CAS  PubMed  Google Scholar 

  44. Ancelin M, Chollet-Martin S, Hervé MA, Legrand C, El Benna J, Perrot-Applanat M (2004) Vascular endothelial growth factor VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism. Lab Invest 84(4):502–12

    Article  CAS  PubMed  Google Scholar 

  45. Christoffersson G, Vågesjö E, Vandooren J, Lidén M, Massena S, Reinert RB, Brissova M, Powers AC, Opdenakker G, Phillipson M (2012) VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 120(23):4653–62

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Podar K1, Anderson KC (2005) The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 15;105(4):1383–95

    Article  Google Scholar 

  47. Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK (1996) During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 2:992–997

    Article  CAS  PubMed  Google Scholar 

  48. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343

    CAS  PubMed  Google Scholar 

  49. Samaniego F, Markham PD, Gendelman R et al (1998) Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi’s sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development. Am J Pathol 152:1433–1443

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Roland CL1, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT, Sadegh L, Sullivan JP, Shames DS, Brekken RA (2009) Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Mol Cancer Ther 8(7):1761–71

    Article  CAS  PubMed  Google Scholar 

  51. Wesolowski R, Markowitz J, Carson WE (2013) Myeloid derived suppressor cells - a new therapeutic target in the treatment of cancer. J Immunother Cancer 1:10

    Article  PubMed Central  PubMed  Google Scholar 

  52. Kao J1, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 77(1):12–9

    Article  PubMed Central  PubMed  Google Scholar 

  53. Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, Ochoa AC (2009) Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69:1553–1560

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Fricke I, Mirza N, Dupont J, Lockhart C, Jackson A, Lee JH, Sosman JA, Gabrilovich D (2007) Treatment of cancer patients with VEGF-Trap overcomes defects in DC differentiation but is insufficient to improve antigen specific immune responses. Clin Cancer Res 13:4840–4848

    Article  CAS  PubMed  Google Scholar 

  55. Fricke I, Mirza N, Dupont J, Lockhart C, Jackson A, Lee JH, Sosman JA, Gabrilovich DI (2007) Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clin Cancer Res 13(16):4840–8

    Article  CAS  PubMed  Google Scholar 

  56. Van Cruijsen H, Hoekman K, Stam AG, van den Eertwegh AJ, Kuenen BC, Scheper RJ, Giaccone G, de Gruijl TD (2007) Defective differentiation of myeloid and plasmacytoid dendritic cells in advanced cancer patients is not normalized by tyrosine kinase inhibition of the vascular endothelial growth factor receptor. Clin Dev Immunol 2007:17315

    PubMed Central  PubMed  Google Scholar 

  57. Li B, Lalani AS, Harding TC, Luan B, Koprivnikar K, Huan Tu G, Prell R, VanRoey MJ, Simmons AD, Jooss K (2006) Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res 12(22):6808–16

    Article  CAS  PubMed  Google Scholar 

  58. Manzoni M, Rovati B, Ronzoni M, Loupakis F, Mariucci S, Ricci V, Gattoni E, Salvatore L, Tinelli C, Villa E, Danova M (2010) Immunological effects of bevacizumab-based treatment in metastatic colorectal cancer. Oncology 79(3–4):187–96

    Article  CAS  PubMed  Google Scholar 

  59. Michielsen AJ, Ryan EJ, O’Sullivan JN (2012) Dendritic cell inhibition correlates with survival of colorectal cancer patients on bevacizumab treatment. Oncoimmunology 1(8):1445–1447

    Article  PubMed Central  PubMed  Google Scholar 

  60. Osada T1, Chong G, Tansik R, Hong T, Spector N, Kumar R, Hurwitz HI, Dev I, Nixon AB, Lyerly HK, Clay T, Morse MA (2008) The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother 57(8):1115–24

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Roland CL1, Lynn KD, Toombs JE, Dineen SP, Udugamasooriya DG, Brekken RA (2009) Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS One 3;4(11):e7669

    Article  Google Scholar 

  62. Terme M1, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J (2013) VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 15;73(2):539–49

    Article  Google Scholar 

  63. Moniz M, Yeatermeyer J, Wu TC (2005) Control of cancers by combining antiangiogenesis and cancer immunotherapy. Drugs Today (Barc) 41(7):471–94

    Article  CAS  Google Scholar 

  64. Johnson BF, Clay TM, Hobeika AC, Lyerly HK, Morse MA (2007) Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert Opin Biol Ther 7(4):449–60

    Article  CAS  PubMed  Google Scholar 

  65. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) AVOREN trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103–11

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Royal College of Surgeons, Beaumont Hospital, Dublin, Ireland

    Yasir Y. Elamin, Sinead Toomey & Bryan T. Hennessy

  2. Department of Medical Oncology, St James’s Hospital, Dublin, Ireland

    Shereen Rafee

Authors
  1. Yasir Y. Elamin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shereen Rafee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sinead Toomey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bryan T. Hennessy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasir Y. Elamin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Elamin, Y.Y., Rafee, S., Toomey, S. et al. Immune Effects of Bevacizumab: Killing Two Birds with One Stone. Cancer Microenvironment 8, 15–21 (2015). https://doi.org/10.1007/s12307-014-0160-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12307-014-0160-8

Keywords

Search

Navigation