Cancer Immunology, Immunotherapy

, Volume 56, Issue 8, pp 1299–1309 | Cite as

Evaluation of a xenogeneic VEGF vaccine in dogs with soft tissue sarcoma

  • Debra Kamstock
  • Robyn Elmslie
  • Douglas Thamm
  • Steven Dow
Original Article


Active immunization against pro-angiogenic growth factors or their receptors is an emerging strategy for controlling tumor growth and angiogenesis. Previous studies in rodent tumor models have indicated that immunization against xenogeneic growth factors is more likely to induce effective anti-tumor responses than immunization against the autologous growth factor. However, the effectiveness or safety of the xenogeneic vaccination approach has not been previously assessed in a clinically relevant outbred, spontaneous tumor model. Therefore, we investigated the safety and anti-tumor and anti-angiogenic effects of a xenogeneic vascular endothelial cell growth factor (VEGF) vaccine in pet dogs with spontaneous cancer. Nine dogs with soft tissue sarcoma were immunized with a recombinant human VEGF vaccine over a 16-week period. The effects of immunization on antibodies to human and canine VEGF, circulating VEGF concentrations, tumor microvessel density (MVD), and tumor growth were assessed. The xenogeneic VEGF vaccine was well-tolerated by all dogs and resulted in induction of humoral responses against both human and canine VEGF in animals that remained in the study long enough to receive multiple immunizations. Three of five multiply immunized dogs also experienced sustained decreases in circulating plasma VEGF concentrations and two dogs had a significant decrease in tumor MVD. The overall tumor response rate was 30% for all treated dogs in the study. We conclude therefore that a xenogeneic VEGF vaccine may be a safe and effective alternative means of controlling tumor growth and angiogenesis.


Canine Cancer Antibodies Immunization Endothelial cell 


  1. 1.
    Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69(Suppl. 3):4–10PubMedCrossRefGoogle Scholar
  2. 2.
    Millanta F, Silvestri G, Vaselli C, Citi S, Pisani G, Lorenzi D et al (2006) The role of vascular endothelial growth factor and its receptor Flk-1/KDR in promoting tumour angiogenesis in feline and canine mammary carcinomas: a preliminary study of autocrine and paracrine loops. Res Vet Sci 81:354–357CrossRefGoogle Scholar
  3. 3.
    Parikh AA, Ellis LM (2004) The vascular endothelial growth factor family and its receptors. Hematol Oncol Clin North Am 18(5):951–971, viiGoogle Scholar
  4. 4.
    Benouchan M, Colombo BM (2005) Anti-angiogenic strategies for cancer therapy (review). Int J Oncol 27(2):563–571PubMedGoogle Scholar
  5. 5.
    Cao Y (2004) Antiangiogenic cancer therapy. Semin Cancer Biol 14(2):139–145PubMedCrossRefGoogle Scholar
  6. 6.
    Cardones AR, Banez LL (2006) VEGF inhibitors in cancer therapy. Curr Pharm Des 12(3):387–394PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69(Suppl. 3):11–16PubMedCrossRefGoogle Scholar
  8. 8.
    Glade-Bender J, Kandel JJ, Yamashiro DJ (2003) VEGF blocking therapy in the treatment of cancer. Expert Opin Biol Ther 3(2):263–276PubMedCrossRefGoogle Scholar
  9. 9.
    Verheul HM, Pinedo HM (2005) Inhibition of angiogenesis in cancer patients. Expert Opin Emerg Drugs 10(2):403–412PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang HT, Bicknell R (2003) Therapeutic inhibition of angiogenesis. Mol Biotechnol 25(2):185–200PubMedCrossRefGoogle Scholar
  11. 11.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342PubMedCrossRefGoogle Scholar
  12. 12.
    Hurwitz H, Kabbinavar F (2005) Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer. Oncology 69(Suppl. 3):17–24PubMedCrossRefGoogle Scholar
  13. 13.
    Salesi N, Bossone G, Veltri E, Di Cocco B, Marolla P, Pacetti U, et al (2005) Clinical experience with bevacizumab in colorectal cancer. Anticancer Res 25(5):3619–3623PubMedGoogle Scholar
  14. 14.
    Sanborn RE, Sandler AB (2006) The safety of bevacizumab. Expert Opin Drug Saf 5(2):289–301PubMedCrossRefGoogle Scholar
  15. 15.
    Rafii S (2002) Vaccination against tumor neovascularization: promise and reality. Cancer Cell 2(6):429–431PubMedCrossRefGoogle Scholar
  16. 16.
    Moniz M, Yeatermeyer J, Wu TC (2005) Control of cancers by combining antiangiogenesis and cancer immunotherapy. Drugs Today (Barc) 41(7):471–494CrossRefGoogle Scholar
  17. 17.
    Li Y, Bohlen P, Hicklin DJ (2003) Vaccination against angiogenesis-associated antigens: a novel cancer immunotherapy strategy. Curr Mol Med 3(8):773–779PubMedCrossRefGoogle Scholar
  18. 18.
    Reisfeld RA, Niethammer AG, Luo Y, Xiang R (2004) DNA vaccines designed to inhibit tumor growth by suppression of angiogenesis. Int Arch Allergy Immunol 133(3):295–304PubMedCrossRefGoogle Scholar
  19. 19.
    Wei YQ, Huang MJ, Yang L, Zhao X, Tian L, Lu Y, et al (2001) Immunogene therapy of tumors with vaccine based on Xenopus homologous vascular endothelial growth factor as a model antigen. Proc Natl Acad Sci USA 98(20):11545–11550PubMedCrossRefGoogle Scholar
  20. 20.
    Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, et al (2002) A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med 8(12):1369–1375PubMedCrossRefGoogle Scholar
  21. 21.
    Liu JY, Wei YQ, Yang L, Zhao X, Tian L, Hou JM, et al (2003) Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2. Blood 102(5):1815–1823PubMedCrossRefGoogle Scholar
  22. 22.
    Lu F, Qin ZY, Yang WB, Qi YX, Li YM (2004) A DNA vaccine against extracellular domains 1–3 of flk-1 and its immune preventive and therapeutic effects against H22 tumor cell in vivo. World J Gastroenterol 10(14):2039–2044PubMedGoogle Scholar
  23. 23.
    Keke F, Hongyang Z, Hui Q, Jixiao L, Jian C (2004) A combination of flk1-based DNA vaccine and an immunomodulatory gene (IL-12) in the treatment of murine cancer. Cancer Biother Radiopharm 19(5):649–657PubMedGoogle Scholar
  24. 24.
    Luo Y, Wen YJ, Ding ZY, Fu CH, Wu Y, Liu JY, et al (2006) Immunotherapy of tumors with protein vaccine based on chicken homologous Tie-2. Clin Cancer Res 12(6):1813–1819PubMedCrossRefGoogle Scholar
  25. 25.
    Plum SM, Holaday JW, Ruiz A, Madsen JW, Fogler WE, Fortier AH (2000) Administration of a liposomal FGF-2 peptide vaccine leads to abrogation of FGF-2-mediated angiogenesis and tumor development. Vaccine 19(9–10):1294–1303PubMedCrossRefGoogle Scholar
  26. 26.
    Scappaticci FA, Nolan GP (2003) Induction of anti-tumor immunity in mice using a syngeneic endothelial cell vaccine. Anticancer Res 23(2B):1165–1172PubMedGoogle Scholar
  27. 27.
    Okaji Y, Tsuno NH, Kitayama J, Saito S, Takahashi T, Kawai K, et al (2004) Vaccination with autologous endothelium inhibits angiogenesis and metastasis of colon cancer through autoimmunity. Cancer Sci 95(1):85–90PubMedCrossRefGoogle Scholar
  28. 28.
    Wei YQ, Wang QR, Zhao X, Yang L, Tian L, Lu Y, et al (2000) Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine. Nat Med 6(10):1160–1166PubMedCrossRefGoogle Scholar
  29. 29.
    Vail DM, MacEwen EG (2000) Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest 18(8):781–792PubMedGoogle Scholar
  30. 30.
    Porrello A, Cardelli P, Spugnini EP (2006) Oncology of companion animals as a model for humans. An overview of tumor histotypes. J Exp Clin Cancer Res 25(1):97–105PubMedGoogle Scholar
  31. 31.
    Clifford CA, Hughes D, Beal MW, Mackin AJ, Henry CJ, Shofer FS, et al (2001) Plasma vascular endothelial growth factor concentrations in healthy dogs and dogs with hemangiosarcoma. J Vet Intern Med 15(2):131–135PubMedCrossRefGoogle Scholar
  32. 32.
    Scheidegger P, Weiglhofer W, Suarez S, Kaser-Hotz B, Steiner R, Ballmer-Hofer K, et al (1999) Vascular endothelial growth factor (VEGF) and its receptors in tumor-bearing dogs. Biol Chem 380(12):1449–1454PubMedCrossRefGoogle Scholar
  33. 33.
    Zaks K, Jordan M, Guth A, Sellins K, Kedl R, Izzo A, et al (2006) Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes. J Immunol 176(12):7335–7345PubMedGoogle Scholar
  34. 34.
    Mueller RS, Veir J, Fieseler KV, Dow SW (2005) Use of immunostimulatory liposome–nucleic acid complexes in allergen-specific immunotherapy of dogs with refractory atopic dermatitis—a pilot study. Vet Dermatol 16(1):61–68PubMedCrossRefGoogle Scholar
  35. 35.
    Walter CU, Biller BJ, Lana SE, Bachand AM, Dow SW (2006) Effects of chemotherapy on immune responses in dogs with cancer. J Vet Intern Med 20(2):342–347PubMedCrossRefGoogle Scholar
  36. 36.
    Wergin MC, Kaser-Hotz B (2004) Plasma vascular endothelial growth factor (VEGF) measured in seventy dogs with spontaneously occurring tumours. In Vivo 18(1):15–19PubMedGoogle Scholar
  37. 37.
    Kamstock D, Guth A, Elmslie R, Kurzman I, Liggitt D, Coro L, et al (2006) Liposome–DNA complexes infused intravenously inhibit tumor angiogenesis and elicit antitumor activity in dogs with soft tissue sarcoma. Cancer Gene Ther 13(3):306–317PubMedCrossRefGoogle Scholar
  38. 38.
    Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang X, et al (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11(9):992–997PubMedGoogle Scholar
  39. 39.
    Verheul HM, Hoekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ, et al (1997) Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3(12 Pt 1):2187–2190PubMedGoogle Scholar
  40. 40.
    Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, et al (1998) Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 77(6):956–964PubMedGoogle Scholar
  41. 41.
    Webb NJ, Bottomley MJ, Watson CJ, Brenchley PE (1998) Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci (Lond) 94(4):395–404Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Debra Kamstock
    • 1
  • Robyn Elmslie
    • 3
  • Douglas Thamm
    • 2
  • Steven Dow
    • 1
    • 2
  1. 1.Department of Microbiology, Immunology, and PathologyColorado State UniversityFt CollinsUSA
  2. 2.Department of Clinical Sciences, Animal Cancer CenterColorado State UniversityFt CollinsUSA
  3. 3.Veterinary Cancer SpecialistsEnglewoodUSA

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