Non-invasive in vivo monitoring of trackable viruses expressing soluble marker peptides

Peng, Kah Whye; Facteau, Suzanne; Wegman, Troy; O’Kane, Dennis J.; Russell, Stephen J.

doi:10.1038/nm0502-527

Cited by 155 publications

(157 citation statements)

References 19 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…19 Based on promising preclinical efficacy studies in an ovarian cancer model, 14 the virus is currently undergoing phase I clinical testing in patients with advanced ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

“…19 To test this hypothesis, we weighed both i.p. tumors and subcutaneous injection site tumors of MV-CEA-treated animals at the time of euthanasia, and plotted these tumor weights against the plasma level of CEA determined at the same time (Figure 3).…”

Section: Correlations Between Plasma Carcinoembryonic Antigen and Intmentioning

confidence: 99%

“…[15][16][17][18] MV-CEA is derived from an attenuated strain of measles virus belonging to the Edmonston vaccine lineage (MV-Edm), and its inserted transgene codes for the soluble extracellular domain of human CEA, which serves as an inert soluble marker to facilitate noninvasive monitoring of virus spread in vivo. 19 MV-CEA-infected cells release CEA into body fluids, and the circulating level of CEA, which can be easily measured, provides a convenient readout to determine if the number of virus-infected cells in the body is increasing or decreasing over time. Carcinoembryonic antigen is a well-established clinical marker that is used to monitor the growth of certain types of tumors, but CEA levels are rarely elevated in patients with ovarian cancer, making it a potentially suitable, nonimmunogenic marker for tracking virus propagation in this disease.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

Hadac

et al. 2006

Cancer Gene Ther

View full text Add to dashboard Cite

Because of their ability to replicate, the dose-response relationships of oncolytic viruses cannot easily be predicted. To better understand the pharmacokinetics of virotherapy in relation to viral dose and schedule, we administered MV-CEA intraperitoneally in an orthotopic mouse model of ovarian cancer. MV-CEA is an attenuated oncolytic measles virus engineered to express soluble human carcinoembryonic antigen (CEA), and the virus is currently undergoing phase I clinical testing in patients with ovarian cancer. Plasma CEA levels correlate with numbers of virus-infected tumor cells at a given time, and were used as a surrogate to monitor the profiles of viral gene expression over time. The antineoplastic activity of single-or multiple-dose MV-CEA was apparent over a wide range of virus doses (10 3 -10 8 TCID 50 ), with little reduction in observed antitumor efficacy, even at the lowest tested dose. However, analysis of CEA profiles of treated mice was highly informative, illustrating the variability in virus kinetics at different dose levels. The highest doses of virus were associated with higher initial levels of tumor cell killing, but the final outcome of MV-CEA therapy at all dose levels was a partial equilibrium between virus and tumor, resulting in significant slowing of tumor growth and enhanced survival of the mice.

show abstract

“…19 Based on promising preclinical efficacy studies in an ovarian cancer model, 14 the virus is currently undergoing phase I clinical testing in patients with advanced ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Section: Correlations Between Plasma Carcinoembryonic Antigen and Intmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

Hadac

et al. 2006

Cancer Gene Ther

View full text Add to dashboard Cite

show abstract

“…Measles virus, for example, was first attenuated by serial passage in cultured cells, then genetically engineered to enhance its oncolytic potency and tumor specificity. [98][99][100][101][102] By and large, through a variety of mechanisms that have recently been reviewed [103][104][105][106][107][108][109][110] these clinically tested oncolytic viruses have shown strong specificity for neoplastic tissue.…”

Section: Discussionmentioning

confidence: 99%

History of Oncolytic Viruses: Genesis to Genetic Engineering

2007

View full text Add to dashboard Cite

Since the turn of the nineteenth century, when their existence was first recognized, viruses have attracted considerable interest as possible agents of tumor destruction. Early case reports emphasized regression of cancers during naturally acquired virus infections, providing the basis for clinical trials where body fluids containing human or animal viruses were used to transmit infections to cancer patients. Most often the viruses were arrested by the host immune system and failed to impact tumor growth, but sometimes, in immunosuppressed patients, infection persisted and tumors regressed, although morbidity as a result of the infection of normal tissues was unacceptable. With the advent of rodent models and new methods for virus propagation, there were numerous attempts through the 1950s and 1960s to force the evolution of viruses with greater tumor specificity, but success was limited and many researchers abandoned the field. Technology employing reverse genetics later brought about a renewal of interest in virotherapy that allowed the generation of more potent, tumor-specific oncolytics. Here, examination of early oncolytic virotherapy before genetic engineering serves to highlight tremendous advances, yet also hints at ways to penetrate host immune defenses, a significant remaining challenge in modern virotherapy research.

show abstract

“…Construction and characterization of the virus have been previously described. 53 When the virus replicates, CEA expression represents a good surrogate of viral gene expression. Virus was propagated in Vero cells and its titer was determined by 50% endpoint dilution assay as previously described.…”

Section: Viral Productionmentioning

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

Non-invasive in vivo monitoring of trackable viruses expressing soluble marker peptides

Cited by 155 publications

References 19 publications

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

History of Oncolytic Viruses: Genesis to Genetic Engineering

Heat shock protein inhibitors increase the efficacy of measles virotherapy

Contact Info

Product

Resources

About