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

Abstract

Oncolytic virotherapy is an emerging strategy that uses replication-competent viruses to kill tumor cells. We have reported the oncolytic effects of TG6002, a recombinant oncolytic vaccinia virus, in preclinical human xenograft models and canine tumor explants. To assess the safety, biodistribution and shedding of TG6002 administered by the intravenous route, we conducted a study in immune-competent healthy dogs. Three dogs each received a single intravenous injection of TG6002 at 105 PFU/kg, 106 PFU/kg or 107 PFU/kg, and one dog received three intravenous injections at 107 PFU/kg. The injections were well tolerated without any clinical, hematological or biochemical adverse events. Viral genomes were only detected in blood at the earliest sampling time point of one-hour post-injection at 107 PFU/kg. Post mortem analyses at day 35 allowed detection of viral DNA in the spleen of the dog which received three injections at 107 PFU/kg. Viral genomes were not detected in the urine, saliva or feces of any dogs. Seven days after the injections, a dose-dependent antibody mediated immune response was identified. In conclusion, intravenous administration of TG6002 shows a good safety profile, supporting the initiation of clinical trials in canine cancer patients as well as further development as a human cancer therapy.

Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication

“… 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 Distribution is driven primarily by interactions between the virus and the mononuclear phagocytic system (MPS) via a panoply of nonspecific interactions (e.g., sialic acids) and serum factors (e.g., complement and natural antibodies). 15 , 24 , 31 , 32 , 33 , 34 To date, PK/BD studies of OVs have used various methods for measuring virus replication in vivo (e.g., qRT-PCR, infectivity assays, protein reporters, reporter imaging 35 , 36 , 37 , 38 , 39 , 40 , 41 ), which do not easily discern between the input virus disposition and replication. Furthermore, replication impacts both concentration-time (PK/BD) and concentration-effect (PD) profiles, resulting in a bidirectional relationship between PK and PD, which has been alluded to by others.…”

Infection of non-cancer cells: A barrier or support for oncolytic virotherapy?

“…Secondary lymphoid tissue is another common target for the majority of OVs (Figure 2). The increased viral titers in the spleen have been shown for VV, [14][15][16][17][18] VSV, [33][34][35] MG1, 36,37 MV, 39 Ad, 46 reovirus, 28 NDV, 156,157 and for the recently described oncolytic alphavirus M1. 158 Of note, for different viruses, the splenic infection has similar dynamics, reaching a peak within a few hours and gradually decreasing thereafter.…”

“…Spleen and liver are the major filters for circulating pathogens and therefore the detection of VV in these organs may simply reflect the sequestration of the injected virus. Nevertheless, several independent studies demonstrate that VV is found more frequently and with higher titers in the spleen than in the liver, [15][16][17][18] indicating that splenocytes may permit viral replication. Although the infected cells have not been identified yet, it is likely that VV specifically targets marginal metallophilic macrophages (MMMs).…”

“…Oncolytic VV strains are known to infect skin and mucosa, causing pox-like lesions. A papulopustular rash has been documented both in animal studies 15,16,54,194 and clinical trials [5][6][7][8]195 following systemic VV injection. It should be noted that the lesions resolve without sequelae and do not require the interruption of the treatment.…”

Oncolytic Vaccinia Virus Harboring Aphrocallistes vastus Lectin Inhibits the Growth of Hepatocellular Carcinoma Cells

“…The TK-deleted vaccinia virus GLV-1h68 (GL-ONC1) harboring β-galactosidase and β-glucuronidase genes has also undergone clinical trials and showed good efficacy in head and neck squamous-cell carcinoma [8]. Moreover, recombinant vaccinia virus TG6002 with deletions of two genes (TK and ribonucleotide) and insertion of the suicide gene FCU1, is currently being eval-uated in clinical trials [9]. In short, oncolytic vaccinia viruses have shown considerable safety and efficacy in clinical trials.…”