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Research article
Safety studies and viral shedding of intramuscular administration of oncolytic vaccinia virus TG6002 in healthy Beagle dogs
Jérémy Béguin
Ecole Nationale Veterinaire d'Alfort
Corresponding Author
ORCiD: https://orcid.org/0000-0003-2400-8309
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Veterinary Research.
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 x 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.
Keywords
Oncolytic virotherapy, Vaccinia virus, TG6002, FCU1, Cancer, Safety, Canine, Translational research
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This is a list of supplementary files associated with this preprint. Click to download.
- Additionalfile1.xls
Additional file 1: Biochemical analyses of dogs after single intramuscular injection of TG6002. File format: .xls No significant anomalies were noted. Bold numbers refer to values outside the reference interval.
- Additionalfile2.xls
Additional file 2: Biochemical analyses of dogs after three intramuscular injections of TG6002. File format: .xls No significant anomalies were noted. Bold numbers refer to values outside the reference interval.
- Additionalfile3.xls
Additional file 3: Detection of virus shedding by plaque assay after single intramuscular injection of TG6002. File format: .xls Infectious VACV was not detected in blood, urine and saliva samples by plaque assay method from dogs treated with escalating doses of TG6002. All samples were run in triplicate.
- Additionalfile4.xls
Additional file 4: Detection of virus shedding by plaque assay after three intramuscular injections of TG6002. File format: .xls Infectious VACV was not detected in blood, urine and saliva samples by plaque assay from dogs treated with three successive injections of TG6002 at 5 x107 PFU/kg. All samples were run in triplicate.
- Additionalfile5.xls
Additional file 5: Detection of virus shedding by qPCR assay after a single intramuscular injection of TG6002. File format: .xls VACV DNA was not detected in blood, urine and saliva samples by qPCR assay from dogs treated with escalating doses of TG6002. All samples were run in triplicate.
- Additionalfile6.xls
Additional file 6: Detection of virus shedding by qPCR assay after three intramuscular injections of TG6002. File format: .xls VACV DNA was not detected in blood, urine and saliva samples by qPCR assay from dogs treated with three successive injections of TG6002 at 5 x 107 PFU/kg. All samples were run in triplicate.
- ARRIVEGuidelinesChecklistRevised.pdf
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Editorial decision: Major revision
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Review #1 received
Received 08 Jun, 2020
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This preprint is under consideration at BMC Veterinary Research. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Safety studies and viral shedding of intramuscular administration of oncolytic vaccinia virus TG6002 in healthy Beagle dogs
Jérémy Béguin
Ecole Nationale Veterinaire d'Alfort
Corresponding Author
ORCiD: https://orcid.org/0000-0003-2400-8309
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 11 Aug, 2020
Published
On 25 Aug, 2020
No community comments so far
Review #1 received
Received 08 Aug, 2020
Reviewers invited
Invitations sent on 04 Aug, 2020
Reviewer #1 agreed
On 04 Aug, 2020
Editor assigned
On 03 Aug, 2020
Submission checks complete
On 02 Aug, 2020
Editor invited
On 02 Aug, 2020
No comments provided
Editorial decision: Major revision
On 17 Jun, 2020
Review #2 received
Received 10 Jun, 2020
Review #1 received
Received 08 Jun, 2020
Reviewers invited
Invitations sent on 19 May, 2020
Reviewer #1 agreed
On 19 May, 2020
Reviewer #2 agreed
On 19 May, 2020
Editor assigned
On 11 May, 2020
Submission checks complete
On 10 May, 2020
Editor invited
On 10 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Veterinary Research.
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 x 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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5