Safety studies and viral shedding of intramuscular administration of oncolytic vaccinia virus TG6002 in healthy Beagle dogs

Abstract

Background Cancer is a leading cause of mortality for both humans and dogs. As spontaneous canine cancers appear to be relevant models of human cancers, the development of new therapeutic approaches can benefit both species. Oncolytic virotherapy is a promising therapeutic approach for the treatment of cancer. TG6002 is a recombinant oncolytic vaccinia virus deleted in the thymidine kinase and ribonucleotide reductase genes and armed with the suicide gene FCU1 that encodes a protein which catalyses conversion of the non-toxic 5-fluorocytosine into the toxic metabolite 5-fluorouracil. Previous studies have shown the ability of TG6002 to infect and replicate in canine tumor cell lines and its oncolytic potency in cell lines, xenograft models and canine mammary adenocarcinoma explants. Moreover, 5-fluorouracil synthesis has been confirmed in fresh canine mammary adenocarcinoma explants infected with TG6002 with 5-fluorocytosine. This study aims to assess the safety profile and viral shedding after unique or repeated intramuscular injections of TG6002 in healthy Beagle dogs. Results The maximal tolerated dose of TG6002 by intramuscular route was 5 × 107 PFU/kg. Repeated intramuscular administrations of TG6002 at the dose of 5 × 107 PFU/kg seem feasible with no particular adverse events. No clinical or biological adverse effect was observed in the course of the study. Residual TG6002 in blood, saliva, urine and feces of treated dogs was not detected by infectious titer assay and by qPCR, ensuring the safety of the virus for the dogs and their environment. Conclusions These results establish the good tolerability of TG6002 in healthy dogs with undetectable viral shedding after multiple injections. This study supports the initiation of further studies in canine cancer patients to evaluate the oncolytic potential of TG6002 and provides critical data for clinical development of TG6002 as human cancer therapy.

Safety, Biodistribution and Viral Shedding of Oncolytic Vaccinia Virus TG6002 Administered Intravenously in Healthy Beagle Dogs

“…Dogs were sedated by intravenous administration of 0.2 mg/kg butorphanol (Torbugesic, Zoetis, Malakoff, France) and 10 µg/kg medetomidine (Domitor, Orion Corporation, Espoo, Finland). The doses chosen in this study were similar to the doses previously described in the safety study by intramuscular route 24 . Dog 1 received 1 x 10 5 PFU/kg, Dog 2 received 1 x 10 6 PFU/kg, Dog 3 received 1 x 10 7 PFU/kg.…”

“…q-PCR was performed as previously described. 24 Samples were measured in triplicate. The limit of detection for analysis was 15 copies/100 µl for whole blood samples, 30 copies/100 µl for urine, 3,600 copies/g for feces and 400 copies/30 mg for organ samples.…”

“…A study on healthy dogs receiving intramuscular injections of TG6002 demonstrated a safety pro le and the absence of viral shedding 24 . The intratumoral route has been favored for a long time in oncolytic virotherapy.…”