Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model.
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.
Lee
J-H
JH
Department of Radiology, College of Medicine, Dong-A University, Busan, South Korea.
Roh
M-S
MS
Lee
Y-K
YK
Kim
M-K
MK
Han
J-Y
JY
Park
B-H
BH
Trown
P
P
Kirn
D H
DH
Hwang
T-H
TH
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
D016178:Granulocyte-Macrophage Colony-Stimulating Factor