Osteosarcoma cells as carriers to allow antitumor activity of canine oncolytic adenovirus in the presence of neutralizing antibodies

F Alcayaga-Miranda,J J Rojas,R Alemany,J Pastor,M Cascallo

doi:10.1038/cgt.2010.36

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.

Highlights

Osteosarcoma (OSA) is the most common bone tumor affecting the dog, with approximately 8000 new cases diagnosed annually
We explored the potential of using canine tumor cells as carriers for delivery of oncolytic canine adenovirus to tumor sites in a xenograft animal model
An increase in the incidence of cancer in dogs is associated with longer life expectancy resulting from advances in pet nutrition and overall advances in veterinary care

Summary

Introduction

Osteosarcoma (OSA) is the most common bone tumor affecting the dog, with approximately 8000 new cases diagnosed annually. Despite refinements to conventional therapy, the prognosis of dogs with OSA remains poor. Current treatment strategies that combine radical surgery and chemotherapy often do not avoid the development of fatal distant metastatic disease within 2 years of diagnosis and treatment.[1] it is desirable to develop more effective therapies, which may slow or delay the onset of metastatic disease Both metastatic and local diseases have been extensively characterized and are strikingly similar to their human counterpart.[2] canine OSA represents the best-characterized spontaneous animal model for human malignant disease

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Conclusion