title: Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model.
abstract: Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species.
authors.affiliation: Department of Radiology, College of Medicine, Dong-A University, Busan, South Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Lee
authors.forename: M-S
authors.initials: MS
authors.lastname: Roh
authors.forename: Y-K
authors.initials: YK
authors.lastname: Lee
authors.forename: M-K
authors.initials: MK
authors.lastname: Kim
authors.forename: J-Y
authors.initials: JY
authors.lastname: Han
authors.forename: B-H
authors.initials: BH
authors.lastname: Park
authors.forename: P
authors.initials: P
authors.lastname: Trown
authors.forename: D H
authors.initials: DH
authors.lastname: Kirn
authors.forename: T-H
authors.initials: TH
authors.lastname: Hwang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D011212:Poxviridae / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor