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Oncolytic Virotherapy with an HSV Amplicon Vector Expressing Cancer Gene Therapy (2007) 14, 918–926 r 2007 Nature Publishing Group All rights reserved 0929-1903/07 $30.00 www.nature.com/cgt ORIGINAL ARTICLE Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte–macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus S-i Kohno1,2, C Luo1,2, A Nawa3, Y Fujimoto4, D Watanabe5, F Goshima1, T Tsurumi6 and Y Nishiyama1 1Department of Virology, Graduate School of Medicine, Nagoya University, Nagoya, Japan; 2Research Division, M’s Science Corporation, Kobe, Japan; 3Department of Obstetrics and Genecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan; 4Department of Otorhinolaryngology, Graduate School of Medicine, Nagoya University, Nagoya, Japan; 5Department of Dermatology, Aichi Medical University, Aichi, Japan and 6Division of Virology, Aichi Cancer Center Research Institute, Nagoya, Japan Direct viral infection of solid tumors can cause tumor cell death, but these techniques offer the opportunity to express exogenous factors to enhance the antitumor response. We investigated the antitumor effects of a herpes simplex virus (HSV) amplicon expressing mouse granulocyte–macrophage colony-stimulating factor (mGM-CSF) using the replication-competent HSV type 1 mutant HF10 as a helper virus. HF10-packaged mGM-CSF-expressing amplicon (mGM-CSF amplicon) was used to infect subcutaneously inoculated murine colorectal tumor cells (CT26 cells) and the antitumor effects were compared to tumors treated with only HF10. The mGM-CSF amplicon efficiently replicated in CT26 cells with similar oncolytic activity to HF10 in vitro. However, when mice subcutaneously inoculated with CT26 cells were intratumorally injected with HF10 or mGM-CSF amplicon, greater tumor regression was seen in mGM-CSF amplicon-treated animals. Furthermore, mGM-CSF amplicon treatment prolonged mouse survival. Immunohistochemical analysis revealed increased inflammatory cell infiltration in the solid tumor in the mGM-CSF amplicon-treated animals. These results suggest that expression of GM-CSF enhances the antitumor effects of HF10, and HF10- packaged GM-CSF-expressing amplicon is a promising agent for the treatment of subcutaneous tumors. Cancer Gene Therapy (2007) 14, 918–926; doi:10.1038/sj.cgt.7701070; published online 10 August 2007 Keywords: HSV amplicon; HF10; oncolytic virotherapy; GM-CSF Introduction more, the HSV-encoded thymidine kinase can enhance the antitumor effect of virotherapy using a ‘suicide gene Genetically altered, replication-competent viruses have therapy’ approach by treating with the thymidine kinase recently been developed and used as novel anticancer inhibitor ganciclovir. Currently, a number of oncolytic agents.1,2 The use of highly attenuated viruses that HSV strains have been developed for oncolytic viro- 4 5–8 9 selectively replicate in and kill tumor cells is called therapy. Among these, G207 1716 and NV1020 have ‘oncolytic viral therapy’ or ‘oncolytic virotherapy’. been extensively investigated and used in clinical trials. Although several different viruses have been used for The combination of oncolytic HSV with chemo- 10–13 14–17 oncolytic virotherapy, most studies have used herpes therapeutic agents, radiation or immunostimula- 18 simplex virus (HSV) or adenovirus as oncolytic viruses.3 tory cytokines has recently been studied in attempts to HSV is particularly appealing as an oncolytic virus. increase the efficacy of replication-competent oncolytic HSV infects a wide range of cells causing degenerative HSV. Other approaches using HSV as an antitumor agent changes and cell death. The virus preferentially replicates have been undertaken including the expression of in dividing cells, and recombinant virus expressing immunostimulatory cytokines using disabled infectious 19,20 exogenous genes is relatively easy to produce. Further- single cycle (DISC) HSV. Additionally, a mutant HSV encoding granulocyte–macrophage colony-stimulat- ing factor (GM-CSF),21 and HSV amplicons expressing Correspondence: Professor Y Nishiyama, Department of Virology, 22–25 Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, exogenous genes have also been described. HSV Showa-ku, Nagoya 466-8550, Japan. amplicon vectors are plasmids containing an HSV origin E-mail: [email protected] of replication and packaging sequence. These vectors Received 15 September 2006; revised 5 April 2007; accepted 19 April replicate in the presence of HSV gene products and are 2007; published online 10 August 2007 packed together in the HSV virion.26,27 Thus, the Oncolytic virotherapy with GM-CSF HSV amplicon S-i Kohno et al 919 resultant virus (HSV amplicon) consists of HSV’s between EcoRI and BamHI sites. The mGM-CSF cDNA envelope, tegument and capsid surrounding the viral was isolated using the HindIII and BamHI sites and DNA and recombinant DNA plasmid. cloned into the pHGCX vector as a transgene driven GM-CSF is a potent immune stimulator promoting the by the cytomegalovirus promoter. The mGM-CSF-expres- differentiation of progenitor cells to dendritic cells (DCs), sing HSV amplicon vector was designated as the central antigen-presenting cell responsible for indu- pHGCXmGM-CSF. Packaging of the HSV-1 amplicon cing an adaptive immune response.28,29 Thus, exogenous vector into HSV-1 HF10 virions was performed as expression of GM-CSF by an HSV amplicon could follows. COS-7 cells (3 Â 105) were seeded in a 35 mm potentially promote the induction of an antitumor dish, and, after an overnight incubation, cells were immune response to enhance the oncolytic effects of transfected with 4 mg of pHGCXmGM-CSF or pHGCX HSV. We previously reported that HF10, a highly using Lipofectamine 2000 (Invitrogen, Carisbad, CA), attenuated replication-competent HSV mutant, has a according to the manufacturer’s instructions. Two hours potent antitumor effect in various tumor models.30–34 after transfection, the transfected cells were infected with Moreover, a phase I/II clinical study was performed HF10 at MOI 0.3. The HF10-packaged pHGCXmGM- examining the oncolytic effects of HF10 on recurrent CSF (termed as mGM-CSF amplicon) or HF10-packaged breast cancer.35 Therefore, we investigated the ability of pHGCX (empty amplicon) were harvested when a an HSV amplicon expressing mouse GM-CSF (mGM- complete cytopathic effect occurred. After freezing and CSF) using replication-competent HF10 as a helper virus thawing three times and the elimination of cell debris, the to control the growth of mouse colorectal tumor cells in supernatants were collected and stored at À801C. Titers both in vitro and in vivo models. of helper virus particles were determined by plaque assay using Vero cells and expressed as plaque forming units (PFU)/ml. Titers of the mGM-CSF amplicon or empty amplicon were determined by infecting Vero cells with Materials and methods serial dilutions of the amplicon stockin the presence of Cell lines and virus 10 m ganciclovir. After 24 h, the number of green CT26 cells were obtained from American Type Culture fluorescent cells was counted using a fluorescence micro- Collection (Rockville, MD). African green monkey scope and expressed as transduction units. kidney cells (Vero and COS-7) were obtained from Riken Cell Bank(Tsukuba,Ibaragi, Japan). CT26 is a colon Immunoblotting epithelial tumor induced by intrarectal injections of CT26 cells were seeded in 35 mm dishes and infected with N-nitroso-N-methylurethane in BALB/c mice. CT26 cells HF10, empty amplicon and mGM-CSF amplicon at MOI were maintained in RPMI 1640 containing 10% fetal 1. Cells were incubated for 72 h and supernatants were bovine serum, 100 U/ml penicillin and 100 mg/ml strepto- harvested. After 20 ml of supernatant was mixed with 20 ml mycin. Vero cells were grown in Eagle’s minimum of sample buffer containing sodium dodecyl sulfate essential medium (MEM) containing 5% calf serum and (SDS), the mixture was heated at 1001C for 2 min and 60 mg/ml kanamycin. COS-7 cells were maintained in then cooled on ice. A total of 40 ml supernatants were Dulbecco’s MEM containing 10% fetal bovine serum, separated by 15% SDS-polyacrylamide gel electropho- 100 U/ml penicillin and 100 mg/ml streptomycin. All cells resis and transferred onto a nitrocellulose membrane. were maintained in a 5% CO2 humidified incubator at Nonspecific binding was blocked overnight at 41C with 371C. phosphate-buffered saline with 0.05% Tween 20 (PBS-T) HF10 is a non-selected clone derived from the containing 5% skim milk. The membrane was incubated 30 laboratory HSV type 1 (HSV-1) strain HF. The with rabbit anti-mGM-CSF antiserum (Sigma-Aldrich, properties of HF10 have been previously described.30 Saint Louis, MI) for 1 h followed by washing three times Briefly, the HF10 genome is characterized by a 3.9 kb in PBS-T. The membrane was then incubated with deletion in the right end of the unique sequence L (UL)/ horseradish peroxidase-conjugated goat anti-rabbit internal repeat L (IRL) junction, and a 2.3 kb deletion secondary antiserum (Biosource International, Camarillo, and extensive gene rearrangements at the left end of the L CA) for 1 h at room temperature. Following three washes segment. HF10 was propagated in Vero cells at a with PBS-T, the protein bands were visualized with ECL multiplicity of infection (MOI) of 0.03 at 371C. Virus Western Blotting Analysis System (Amersham Bios- titers were determined using plaque assays on Vero cells. ciences UK, Little Chalfont, UK) and exposed to Fuji film (Fuji Photo Film, Tokyo, Japan). mGM-CSF-expressing HSV-1 amplicon vector and amplicon production In vitro experiments The mGM-CSF-expressing amplicon vector was con- CT26 cells were infected with HF10, empty amplicon structed as follows. The HSV amplicon plasmid, pHGCX, (packaged into HF10 virions) or mGM-CSF amplicon was obtained from Dr Yoshinaga Saeki (Massachusetts (packaged into HF10 virions) at MOI 1 in 35 mm dishes. General Hospital, Charlestown, MA). pBluescript Transduction units of empty amplicon or mGM-CSF SKII þ mGM-CSF vector obtained from Dr Hirofumi amplicon were 6.01 Â 104 and 7.42 Â 104, respectively.
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