Abstract
Osteosarcoma (OSA) is the most common bone tumor affecting the dog. The veterinary options for therapeutic management of OSA are limited and prognosis for such patients is poor. Oncolytic adenoviruses are attractive tools for experimental therapeutics as they can replicate and spread within tumors to directly induce tumor destruction. However, a major impediment to systemic oncolytic adenoviruses injection is the presence of pre-existing neutralizing antibodies (Nabs). In this study, we investigated the effect of a replication-selective canine adenovirus (OCCAV) to treat OSA in the presence of Nabs and the use of canine OSA cells as carrier vehicles for evading Nabs. Our systemic biodistribution data indicated that canine tumor cells could successfully reach the tumor site and deliver OCCAV to tumor cells in an immunized mice model. Furthermore, the use of carrier cells also reduced adenovirus uptake by the liver. Importantly, OCCAV alone was not effective to control tumor growth in a pre-immunized xenograft mouse model. On the contrary, systemic antitumoral activity of carrier-cell OCCAV was evident even in the presence of circulating antibodies, which is a relevant result from a clinical point of view. These findings are of direct translational relevance for the future design of canine clinical trials.
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References
Dernell Sr WS, Withrow SJ . Tumors of the skeletal system. In: Withrow SJ ME, ed. Small Animal Clinical Oncology. Saunders, Elsevier: Philadelphia, 2001: 378–417.
Mueller F, Fuchs B, Kaser-Hotz B . Comparative biology of human and canine osteosarcoma. Anticancer Res 2007; 27 (1A): 155–164.
Russell SJ . Replicating vectors for cancer therapy: a question of strategy. Semin Cancer Biol 1994; 5: 437–443.
Garber K . China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst 2006; 98: 298–300.
Hemminki A, Kanerva A, Kremer EJ, Bauerschmitz GJ, Smith BF, Liu B et al. A canine conditionally replicating adenovirus for evaluating oncolytic virotherapy in a syngeneic animal model. Mol Ther 2003; 7: 163–173.
Smith BF, Curiel DT, Ternovoi VV, Borovjagin AV, Baker HJ, Cox N et al. Administration of a conditionally replicative oncolytic canine adenovirus in normal dogs. Cancer Biother Radiopharm 2006; 21: 601–606.
Lyons M, Onion D, Green NK, Aslan K, Rajaratnam R, Bazan-Peregrino M et al. Adenovirus type 5 interactions with human blood cells may compromise systemic delivery. Mol Ther 2006; 14: 118–128.
Power AT, Wang J, Falls TJ, Paterson JM, Parato KA, Lichty BD et al. Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity. Mol Ther 2007; 15: 123–130.
Ilett EJ, Prestwich RJ, Kottke T, Errington F, Thompson JM, Harrington KJ et al. Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity. Gene Ther 2009; 16: 689–699.
Hamada K, Desaki J, Nakagawa K, Zhang T, Shirakawa T, Gotoh A et al. Carrier cell-mediated delivery of a replication-competent adenovirus for cancer gene therapy. Mol Ther 2007; 15: 1121–1128.
Greene C . Infectious canine hepatitis and canine acidophil cell hepatitis. In: Greene C, ed. Infectious Disease of the Dog and Cat. Vol 2. WB Saunders: Philadelphia, 1998.
Gahery-Segard H, Farace F, Godfrin D, Gaston J, Lengagne R, Tursz T et al. Immune response to recombinant capsid proteins of adenovirus in humans: antifiber and anti-penton base antibodies have a synergistic effect on neutralizing activity. J Virol 1998; 72: 2388–2397.
Fidler IJ . The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003; 3: 453–458.
Netland PA, Zetter BR . Organ-specific adhesion of metastatic tumor cells in vitro. Science 1984; 224: 1113–1115.
Raykov Z, Balboni G, Aprahamian M, Rommelaere J . Carrier cell-mediated delivery of oncolytic parvoviruses for targeting metastases. Int J Cancer 2004; 109: 742–749.
Raykov Z, Rommelaere J . Potential of tumour cells for delivering oncolytic viruses. Gene Ther 2008; 15: 704–710.
Coukos G, Courreges MC, Benencia F . Intraperitoneal oncolytic and tumor vaccination therapy with replication-competent recombinant virus: the herpes paradigm. Curr Gene Ther Apr 2003; 3: 113–125.
Guo ZS, Thorne SH, Bartlett DL . Oncolytic virotherapy: molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses. Biochim Biophys Acta Apr 2008; 1785: 217–231.
Garcia-Castro J, Martinez-Palacio J, Lillo R, García-Sánchez F, Alemany R, Madero L et al. Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors. Cancer Gene Ther 2005; 12: 341–349.
Gimenez-Alejandre M, Cascallo M, Bayo-Puxan N, Alemany R . Coagulation factors determine tumor transduction in vivo. Hum Gene Ther 2008; 19: 1415–1419.
Cascallo M, Gros A, Bayo N, Serrano T, Capella G, Alemany R . Deletion of VAI and VAII RNA genes in the design of oncolytic adenoviruses. Hum Gene Ther 2006; 17: 929–940.
Bayo-Puxan N, Cascallo M, Gros A, Huch M, Fillat C, Alemany R . Role of the putative heparan sulfate glycosaminoglycan-binding site of the adenovirus type 5 fiber shaft on liver detargeting and knob-mediated retargeting. J Gen Virol 2006; 87 (Part 9): 2487–2495.
Hogge GS, Burkholder JK, Culp J, Albertini MR, Dubielzig RR, Yang NS et al. Preclinical development of human granulocyte-macrophage colony-stimulating factor-transfected melanoma cell vaccine using established canine cell lines and normal dogs. Cancer Gene Ther 1999; 6: 26–36.
Alemany R . Cancer selective adenoviruses. Mol Aspects Med 2007; 28: 42–58.
Zaiss AK, Vilaysane A, Cotter MJ, Clark SAV, Meijndert HC, Colarusso P et al. Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response. J Immunol 2009; 182: 7058–7068.
Alemany R, Balague C, Curiel DT . Replicative adenoviruses for cancer therapy. Nat Biotechnol Jul 2000; 18: 723–727.
Power AT, Bell JC . Taming the Trojan horse: optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy. Gene Ther 2008; 15: 772–779.
Hong SS, Habib NA, Franqueville L, Jensen S, Boulanger PA . Identification of adenovirus (ad) penton base neutralizing epitopes by use of sera from patients who had received conditionally replicative ad (addl1520) for treatment of liver tumors. J Virol 2003; 77: 10366–10375.
Plaksin D, Porgador A, Vadai E, Feldman M, Schirrmacher V, Eisenbach L . Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 1994; 59: 796–801.
Kremer EJ, Boutin S, Chillon M, Danos O . Canine adenovirus vectors: an alternative for adenovirus-mediated gene transfer. J Virol 2000; 74: 505–512.
Acknowledgements
We thank Blanca Luena for technical assistance. FAM was supported by pre-doctoral fellowship (FI) UAB2006-00271 granted by the Universitat Autònoma de Barcelona. This work was supported by BIO2008-04692-Co3-01 from the Ministerio de Ciencia y Tecnología of the Government of Spain (RA), EU 6th FP research contract 18700 (Theragpox, RA), 2005 SGR 00727 from the Departament d’Universitats, Recerca I Societat de la Informació of the Generalitat de Catalunya and by Mutua Madrileña Medical Research Foundation. RA belongs to the Network of Cooperative Research on Cancer (C03-10), Instituto de Salud Carlos III of the Ministerio de Sanidad y Consumo, Government of Spain.
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Alcayaga-Miranda, F., Cascallo, M., Rojas, J. et al. Osteosarcoma cells as carriers to allow antitumor activity of canine oncolytic adenovirus in the presence of neutralizing antibodies. Cancer Gene Ther 17, 792–802 (2010). https://doi.org/10.1038/cgt.2010.36
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DOI: https://doi.org/10.1038/cgt.2010.36
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