Productive Replication of Human Adenovirus Type 5 in Canine Cells

Abstract

Development of immunocompetent patient-like models that allow direct analysis of human adenovirus-based conditionally replicative adenoviruses (CRAds) would be beneficial for the advancement of these oncolytic agents. To this end, we explored the possibility of cross-species replication of human adenovirus type 5 (Ad5) in canine cells. With a panel of canine tumor cell lines of both epithelial and mesenchymal derivations, we demonstrate that human Ad5 can productively infect canine cells. Since the biological behavior and clinical presentation of certain dog tumors closely resemble those of their human counterparts, our results raise the possibility of exploiting canine models for preclinical analysis of candidate CRAd agents designed for human virotherapy.Conditionally replicative adenovirus (CRAd) agents represent a promising new therapeutic approach for cancer. This strategy is based on the application of an adenovirus engineered to selectively replicate in tumor targets (1, 3). This tumor-selective replication forms the functional basis of the antineoplastic effect achieved by direct target cell killing in a process termed oncolysis (1, 16). The exceptional promise of these agents has predicated their rapid transition to human phase I clinical trials whereby the overall safety of this approach has been validated (15,22,28). Nonetheless, the very limited indications of efficacy to this point have established the requirement for further design advances to enhance CRAd antitumor potency (11,15,20,23).Critical to the derivation of advanced-generation CRAds is the development of model systems capable of delineating key therapeutic indices. For CRAds, the fact that human adenoviruses can accomplish only abortive replication in murine targets (7-9, 17) has restricted the preclinical toxicity information that may be derived from SCID-xenograft model systems typically used for efficacy analysis. Further, these immunologically incompetent models cannot provide useful information with respect to CRAd immunobiology and vector-host interactions. On this basis, it is clear that there exists a field-wide need for immunocompetent syngeneic models for full analysis of candidate CRAd agents. Several recent reports have described model systems to achieve these goals. Hemminki et al. have exploited the availability of human-like canine models of cancer (31) for the evaluation of CRAd agents derived from canine adenoviruses (12,15,31). This approach potentially allows the study of vector-host interactions in an immunocompetent host in the context of a patient-like cancer model. CRAd constructs based on canine adenoviruses, however, may embody substantial biological differences from human adenovirus-based CRAds. Alternatively, an approach has been proposed whereby adapted murine cells permissive for limited human adenovirus replication are transplanted into an immunocompetent mouse host (10,29). Whereas this approach may allow direct analysis of human adenovirus-based CRAds in a murine system, this transplant model does not repre...

Characterization and evaluation of a new oncolytic Vaccinia Virus strain LIVP6.1.1 for canine cancer therapy

“…Tumors were generated by implanting 1 × 10 6 STSA-1 canine soft tissue sarcoma cells subcutaneously into the right hind leg of 6-to 8-week-old female nude mice (NCI/Hsd/Athymic Nude-Foxn1 nu ). Five weeks post implantation, all mice developed tumors with volumes of 600 to 1000 mm 3 . We have chosen mice with larger tumors for virus injection since this late stage of the tumor development is more representative and interesting for the clinical praxis.…”

“…As shown in Figure 3A, the virus treatment led to a significant decrease in STSA-1 tumor growth in all virus-treated mice compared with PBS control mice. Due to excessive tumor burden (> 3000 mm 3 ), all animals in the control PBS group were euthanized after 14 dpi.…”

“…Furthermore, a clinical trial with canine cancer patients has already been started. [3][4][5] canine distemper virus 6 and vaccinia virus strains, namely GLV-1h68, LIVP1.1.1 [7][8][9] and GLV-1h109 10 have been successfully tested for canine cancer therapy in preclinical settings (for review, see refs. 11 and 12).…”

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“…Several animal models have been proposed that are to some extent permissive for human Ad replication, including cotton rats (30,31), pigs (32), dogs (33), and Syrian hamsters (34)(35)(36). However, these studies did not address replication of Ad under conditions of immunosuppression, as is observed in transplant patients.…”

Evolving gene therapy approaches for osteosarcoma using viral vectors: Review

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