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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, developing new therapeutic approaches could benefit both species. Oncolytic virotherapy is a promising therapeutic approach in cancer treatment. 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 the 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 demonstrated 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 at assessing the safety profile and viral shedding after unique or repeated intramuscular injections of TG6002 in seven healthy Beagle dogs. RESULTS:Repeated intramuscular administrations of TG6002 at the dose of 5?×?107 PFU/kg resulted in no clinical or biological adverse effects. Residual TG6002 in blood, saliva, urine and feces of treated dogs was not detected by infectious titer assay nor by qPCR, ensuring the safety of the virus in 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 a human cancer therapy.

SUBMITTER: Beguin J

PROVIDER: S-EPMC7446062 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Béguin Jérémy J Nourtier Virginie V Gantzer Murielle M Cochin Sandrine S Foloppe Johann J Balloul Jean-Marc JM Laloy Eve E Tierny Dominique D Klonjkowski Bernard B Quemeneur Eric E Maurey Christelle C Erbs Philippe P

BMC veterinary research 20200825 1

<h4>Background</h4>Cancer is a leading cause of mortality for both humans and dogs. As spontaneous canine cancers appear to be relevant models of human cancers, developing new therapeutic approaches could benefit both species. Oncolytic virotherapy is a promising therapeutic approach in cancer treatment. 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 th ...[more]

PMID: 32843040

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Project description:BackgroundPimobendan is widely used for the treatment of dogs with heart failure via the oral route. A new injectable form of pimobendan is now available and its potential usefulness via intravenous route has been recently demonstrated in dogs. However, the cardiovascular effects of intramuscular (IM) administration of injectable pimobendan have not been investigated yet.HypothesisIM administration of pimobendan may have the same hemodynamic effect as the IV route.MethodsSix healthy Beagle dogs underwent a placebo-controlled double-blind crossover study. The early cardiovascular effects after a single dose of IM and IV injections of pimobendan (0.2 ml/kg; Pimo IM and Pimo IV, respectively) were compared to the same volume of IM placebo (Saline IM) in anesthetized dogs. Clinical [heart rate (HR) and blood pressure (BP)] and echocardiographic hemodynamic parameters [left ventricular (LV) inflow waveforms of diastolic early wave (eV), atrial systolic wave (aV), diastolic early mitral ring velocity (e'), peak velocity (pV), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR)] were monitored with 15 min intervals for 120 min.ResultsDiastolic BP decreased significantly at 30 min in Pimo IM compared to Saline IM. Mean eV and CO values significantly increased from 75 min, e' from 60 min, pV from 75 min, and SV from 15 to 120 min, whereas SVR significantly decreased at 30-60 min in Pimo IM compared to those of Saline IM (P < 0.05). Compared with the Pimo IV, eV and pV were significantly lower at 30-60 min (P < 0.05) while SV was significantly higher at 90-105 min in Pimo IM (P < 0.05). Other hemodynamic parameters (BP, HR, SVR, CO, e', and E/e') did not significantly change between Pimo IM and IV.ConclusionsThe hemodynamic effect of pimobendan following IM and IV injection was described. Our results suggested that IM administration of pimobendan is equally comparable and possibly interchangeable with IV administration. This warrant further studies to investigate the clinical effectiveness of IM pimobendan in treating dogs with congestive heart failure or in heart failure cases unable to receive IV or oral administration.

Dataset Information

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

Publications

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

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