Safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding CD40 ligand in laboratory Beagles

Abstract

We evaluated adverse events, biodistribution and shedding of oncolytic vaccinia virus encoding CD40 ligand in two Beagles, in preparation for a phase 1 trial in canine cancer patients. Dog 1 received one dose of vaccinia virus and was euthanized 24 hours afterwards, while dog 2 received virus four times once weekly and was euthanized 7 days after that. Dogs were monitored for adverse events and underwent a detailed postmortem examination. Blood, saliva, urine, feces, and organs were collected for virus detection. Dog 1 had mild fever and lethargy while dog 2 experienced a possible seizure 5.5 hours after first virus administration. Viral DNA declined quickly in the blood after virus administration in both dogs but was still detectable 1 week later by quantitative polymerase chain reaction. Only samples taken directly after virus infusion contained infectious virus. Small amounts of viral DNA, but no infectious virus, were detected in a few saliva and urine samples. Necropsies did not reveal any relevant pathological changes and virus DNA was detected mainly in the spleen. The dogs in the study did not have cancer, and thus adverse events could be more common and viral load higher in dogs with tumors which allow viral amplification.

Maraba virus-vectored cancer vaccines represent a safe and novel therapeutic option for cats

“…One pre-clinical study reported by Autio et al . also demonstrated the safety of an oncolytic vaccinia virus in dogs 26 . Dr. Stephen Russell’s group at the Mayo Clinic (Rochester, Minnesota, USA), was the first to characterize oncolytic VSV as a safe monotherapy in dogs 27 .…”

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

“…Even if dogs with induced pock lesions were in close contact with sentinel dogs, none of these control animals developed VACV antibodies, which suggested the absence of viral shedding [24]. In a study with intravenous oncolytic VACV administrations in healthy dogs, the viral load, detected by qPCR, declined quickly in blood samples during the 4 hours after infusion and viral DNA was not detected in feces, saliva and urine samples collected at 1, 2, or 4 days after virus administration [37]. In human clinical trials, viral genome has also been detected in patients' blood after intratumoral administration of oncolytic VACV [19,52].…”

Attenuated Semliki Forest virus for cancer treatment in dogs: safety assessment in two laboratory Beagles

“…In a study with oncolytic adenovirus injected intravenously in healthy dogs infectious virus was not measured, but neutralizing antibodies increased already 4 days after virus administration [ 32 ]. So far, the only dog study in which infectious virus has been recovered after injection was with vaccinia virus, but the virus was recovered only from blood samples taken immediately after the intravenous administration [ 33 ]. Also in that study, neutralizing antibody responses were demonstrated 2 weeks after virus injection.…”

“…Oncolytic adenovirus has so far showed excellent safety in tumor-bearing [ 39 ] and healthy dogs [ 32 ], likely owing in part to its restricted species tropism. Oncolytic vaccinia virus was reported to induce mild fever and an apparent epileptiformic seizure in healthy Beagles [ 33 ]. Several mild to moderate adverse events and one severe liver toxicity resulting in euthanasia were reported in healthy Beagle dogs receiving high-dose oncolytic vesicular stomatitis virus [ 31 ].…”