A pRb-responsive, RGD-modified, and hyaluronidase-armed canine oncolytic adenovirus for application in veterinary oncology.
Human and canine cancer share similarities such as genetic and molecular aspects, biological complexity, tumor epidemiology, and targeted therapeutic treatment. Lack of good animal models for human adenovirotherapy has spurred the use of canine adenovirus 2-based oncolytic viruses. We have constructed a canine oncolytic virus that mimics the characteristics of our previously published human adenovirus ICOVIR17: expression of E1a controlled by E2F sites, deletion of the pRb-binding site of E1a, insertion of an RGD integrin-binding motif at the fiber Knob, and expression of hyaluronidase under the major late promoter/IIIa protein splicing acceptor control. Preclinical studies showed selectivity, increased cytotoxicity, and strong hyaluronidase activity. Intratumoral treatment of canine osteosarcoma and melanoma xenografts in mice resulted in inhibition of tumor growth and prolonged survival. Moreover, we treated six dogs with different tumor types, including one adenoma, two osteosarcomas, one mastocitoma, one fibrosarcoma, and one neuroendocrine hepatic carcinoma. No virus-associated adverse effects were observed, but toxicity associated to tumor lysis, including disseminated intravascular coagulation and systemic failure, was found in one case. Two partial responses and two stable diseases warrant additional clinical testing.
1] Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, Barcelona, Spain [2] Biochemistry and Molecular Biology Department, Autonomous University of Barcelona, Barcelona, Spain.
Eduardo
E
Laborda
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, Barcelona, Spain.
Cristina
C
Puig-Saus
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, Barcelona, Spain.
Alba
A
Rodriguez-García
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, Barcelona, Spain.
Rafael
R
Moreno
VCN Biosciences, Barcelona, Spain.
Manel
M
Cascalló
Animal Medicine and Surgery Department, Fundació Hospital Clínic Veterinari, Autonomous University of Barcelona, Barcelona, Spain.
Josep
J
Pastor
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, Barcelona, Spain.
Ramon
R
Alemany
D006516:Adenoviruses, Canine / Q000235:genetics; D000818:Animals; D004285:Dogs; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000235:genetics / Q000627:therapeutic use; D008545:Melanoma / Q000235:genetics / Q000628:therapy* / Q000662:veterinary; D051379:Mice; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics / Q000628:therapy* / Q000662:veterinary; D023041:Xenograft Model Antitumor Assays
D006821:Hyaluronoglucosaminidase