Engineered measles virus as a novel oncolytic viral therapy system for hepatocellular carcinoma

Blechacz, Boris; Splinter, Patrick L.; Greiner, Suzanne; Myers, Rae; Peng, Kah Whye; Federspiel, Mark J.; Russell, Stephen J.; LaRusso, Nicholas F.

doi:10.1002/hep.21437

Cited by 105 publications

(86 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9 Another application is the combination of the imaging and therapeutic potential of the hNIS transgene. 35 Oncolytic recombinant measles viruses encoding hNIS have already been described 36,37 and used to demonstrate the concept of image-guided radiovirotherapy in a pre-clinical model of multiple myeloma. 36 Our work suggests the possibility to extend this concept to adenoviruses.…”

Section: Spect/ct Imaging Of Oncolytic Adenovirusesmentioning

confidence: 99%

SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene

et al. 2007

View full text Add to dashboard Cite

Oncolytic adenoviruses have shown some promise in cancer gene therapy. However, their efficacy in clinical trials is often limited, and additional therapeutic interventions have been proposed to increase their efficacies. In this context, molecular imaging of viral spread in tumours could provide unique information to rationalize the timing of these combinations. Here, we use the human sodium iodide symporter (hNIS) as a reporter gene in wild-type and replication-selective adenoviruses. By design, hNIS cDNA is positioned in the E3 region in a wild-type adenovirus type 5 (AdIP1) and in an adenovirus in which a promoter from the human telomerase gene (RNA component) drives E1 expression (AdAM6). Viruses show functional hNIS expression and replication in vitro and kinetics of spread of the different viruses in tumour xenografts are visualized in vivo using a small animal nano-SPECT/CT camera. The time required to reach maximal spread is 48 h for AdIP1 and 72 h for AdAM6 suggesting that genetic engineering of adenoviruses can affect their kinetics of spread in tumours. Considering that this methodology is potentially clinically applicable, we conclude that hNIS-mediated imaging of viral spread in tumours may be an important tool for combined anticancer therapies involving replicating adenoviruses.

show abstract

Section: Spect/ct Imaging Of Oncolytic Adenovirusesmentioning

confidence: 99%

SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Intratumoral injection of the unmodified MV Edmonston strain or an Edmonston strain derived recombinant MV induced regression of large established human lymphoma xenografts in murine models (Grote et al, 2001). This oncolytic virus has also been reported to have potency against human epithelial ovarian cancer cells in vitro and in vivo, being selectively lytic for the ovarian tumor cells (Peng et al, 2002), hepatocellular carcinoma (Blechacz et al, 2006), or prostate cancer cells (Msaouel et al, 2009b), among others. Russell et al (2010) filed a patent application which describes a method for limiting the growth of cancer cells using an attenuated MV strain.…”

Section: Potential Of Measles Virus For Cancer Therapymentioning

confidence: 99%

Key Parameters of Measles Virus Production for Oncolytic Virotherapy

Weiss

Salzig

Mühlebach³

et al. 2012

American Journal of Biochemistry and Biotechnology

View full text Add to dashboard Cite

Attenuated measles virus has revealed selective tumor cell killing and is currently tested in clinical trials for the therapy of cancer patients. The amount of infectious particles per dose needed for oncolytic therapy can be more than a million times higher compared to vaccination. This requires highly effective production processes which guarantee the measles virus quantities needed for its use in cancer therapy. Referring to measles virus production itself, several factors are influencing process parameters and subsequent virus yields. These factors are medium optimization, feeding of nutrients, an optimal multiplicity of infection, localization of produced virus particles, temperature sensitivity and time of harvest. This review summarizes the available data concerning measles virus production in cell culture and factors influencing the virus yield.

show abstract

“…We have previously demonstrated oncolytic activity of measles virus strains against a variety of tumors including lymphoma, 2 multiple myeloma, 3 ovarian cancer, 4 brain tumors, 6 breast cancer, 7 hepatocellular carcinoma 5 and we are currently testing the engineered measles virus strains MV-CEA and MV-NIS in three phase I/II trials against ovarian cancer, brain tumors and multiple myeloma.…”

Section: Combining Measles Virus With Heat Shock Protein Inhibitors Cmentioning

confidence: 99%

“…1 Antitumor activity of attenuated strains of measles virus derived from the Edmonston vaccine lineage has been demonstrated in models of lymphoma, 2 multiple myeloma, 3 ovarian cancer, 4 hepatocellular carcinoma, 5 glioblastoma multiforme 6 and breast cancer. 7 After infection of tumor cells, the virus causes a very characteristic cytopathic effect, the development of multinucleated giant cells (syncytia).…”

Section: Introductionmentioning

confidence: 99%

Heat shock protein inhibitors increase the efficacy of measles virotherapy

Liu

Erlichman

et al. 2008

Gene Ther

View full text Add to dashboard Cite

Oncolytic measles virus strains have activity against multiple tumor types and are currently in phase I clinical testing. Induction of the heat shock protein 70 (HSP70) constitutes one of the earliest changes in cellular gene expression following infection with RNA viruses including measles virus, and HSP70 upregulation induced by heat shock has been shown to result in increased measles virus cytotoxicity. HSP90 inhibitors such as geldanamycin (GA) or 17-allylaminogeldanamycin result in pharmacologic upregulation of HSP70 and they are currently in clinical testing as cancer therapeutics. We therefore investigated the hypothesis that heat shock protein inhibitors could augment the measles virus-induced cytopathic effect. We tested the combination of a measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) and GA in MDA-MB-231 (breast), SKOV3.IP (ovarian) and TE671 (rhabdomyosarcoma) cancer cell lines. Optimal synergy was accomplished when GA treatment was initiated 6-24 h following MV infection. Western immunoblotting confirmed HSP70 upregulation in combination-treated cells. Combination treatment resulted in statistically significant increase in syncytia formation as compared to MV-CEA infection alone. Clonogenic assays demonstrated significant decrease in tumor colony formation in MV-CEA/GA combination-treated cells. In addition there was increase in apoptosis by 4,6-diamidino-2-phenylindole staining. Western immunoblotting for caspase-9, caspase-8, caspase-3 and poly(ADP-ribose) polymerase (PARP) demonstrated increase in cleaved caspase-8 and PARP. The pan-caspase inhibitor Z-VAD-FMK and caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, protected tumor cells from MV-CEA/GA-induced PARP activation, indicating that apoptosis in combinationtreated cells occurs mainly via the extrinsic caspase pathway. Treatment of normal cells, such as normal human fibroblasts, however, with the MV-CEA/GA combination, did not result in cytopathic effect, indicating that GA did not alter the MV-CEA specificity for tumor cells. One-step viral growth curves, western immunoblotting for MV-N protein expression, QRT-PCR quantitation of MV-genome copy number and CEA levels showed comparable proliferation of MV-CEA in GAtreated vs -untreated tumor cells. Rho activation assays and western blot for total RhoA, a GTPase associated with the actin cytoskeleton, demonstrated decrease in RhoA activation in combination-treated cells, a change previously shown to be associated with increase in paramyxovirus-induced cell-cell fusion. The enhanced cytopathic effect resulting from measles virus/GA combination supports the translational potential of this approach in the treatment of cancer.

show abstract

Engineered measles virus as a novel oncolytic viral therapy system for hepatocellular carcinoma

Abstract: The oncolytic measles virus Edmonston strain (MV-Edm

Cited by 105 publications

References 62 publications

SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene

SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene

Key Parameters of Measles Virus Production for Oncolytic Virotherapy

Heat shock protein inhibitors increase the efficacy of measles virotherapy

Contact Info

Product

Resources

About