Preclinical Evaluation of the Oncolytic Vaccinia Virus TG6002 by Translational Research on Canine Breast Cancer

Abstract

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 , which encodes a bifunctional chimeric protein that efficiently catalyzes the direct conversion of the nontoxic 5-fluorocytosine into the toxic metabolite 5-fluorouracil. In translational research, canine tumors and especially mammary cancers are relevant surrogates for human cancers and can be used as preclinical models. Here, we report that TG6002 is able to replicate in canine tumor cell lines and is oncolytic in such cells cultured in 2D or 3D as well as canine mammary tumor explants. Furthermore, intratumoral injections of TG6002 lead to inhibition of the proliferation of canine tumor cells grafted into mice. 5-fluorocytosine treatment of mice significantly improves the anti-tumoral activity of TG6002 infection, a finding that can be correlated with its conversion into 5-fluorouracil within infected fresh canine tumor biopsies. In conclusion, our study suggests that TG6002 associated with 5-fluorocytosine is a promising therapy for human and canine cancers.

Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

“…TG6002 is armed with the therapeutic gene FCU1 , which encodes a bifunctional chimeric protein that catalyzes the conversion of 5-FC into the toxic metabolites 5-FU and 5-FUMP [ 51 ]. TG6002 has been shown to replicate and exert oncolytic potency in canine cell lines and canine xenograft model [ 52 ]. In murine xenograft models of hepatocarcinoma and colorectal cancer treated with intravenous administration of TG6002 and oral 5-FC, a significant reduction of tumor size and an intratumoral production of 5-FU were reported [ 30 ].…”

“…The lytic properties of TG6002 and the 5-FU synthesis were also assessed on canine mammary tumor explants. In vitro infection of canine mammary carcinoma biopsies with TG6002 led to tumor necrosis and the conversion of 5-FC into 5-FU [ 52 ]. From a clinical trial perspective, a safety study has established the innocuity of multiple intramuscular injections of TG6002 with short term administration of 5-FC in healthy dogs [ 31 ].…”

Safety, biodistribution and viral shedding of oncolytic vaccinia virus TG6002 administered intravenously in healthy beagle dogs

“…Spontaneous canine tumors have been shown to be relevant models for human oncology 20 , 29 – 32 . TG6002 has been shown to replicate and to exert oncolytic potency in canine cell lines and canine xenograft model 33 . The lytic properties of TG6002 were tested on canine mammary tumor explants.…”

“…The lytic properties of TG6002 were tested on canine mammary tumor explants. In vitro infection of canine mammary carcinoma biopsies with TG6002 led to tumor necrosis and the conversion of 5-FC into 5-FU 33 .…”

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

“…The lytic properties of TG6002 were tested on canine mammary tumor explants. In vitro infection of canine mammary carcinoma biopsies with TG6002 led to tumor necrosis and the conversion of 5-FC into 5-FU 23 .…”