Significant Growth Inhibition of Canine Mammary Carcinoma Xenografts following Treatment with Oncolytic Vaccinia Virus GLV-1h68

Gentschev, Ivaylo; Ehrig, Klaas; Donat, Ulrike; Heß, Michael; Rudolph, Stephan; Chen, Nanhai; Yu, Yong A.; Zhang, Qian; Bullerdiek, Jörn; Nolte, Ingo; Stritzker, Jochen; Szalay, Aladar A.

doi:10.1155/2010/736907

Cited by 30 publications

(47 citation statements)

References 18 publications

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“…Furthermore, a clinical trial with canine cancer patients has already been started. [3][4][5] canine distemper virus 6 and vaccinia virus strains, namely GLV-1h68, LIVP1.1.1 [7][8][9] and GLV-1h109 10 have been successfully tested for canine cancer therapy in preclinical settings (for review, see refs. 11 and 12).…”

Section: Introductionmentioning

confidence: 99%

Characterization and evaluation of a new oncolytic Vaccinia Virus strain LIVP6.1.1 for canine cancer therapy

et al. 2013

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Section: Introductionmentioning

confidence: 99%

Characterization and evaluation of a new oncolytic Vaccinia Virus strain LIVP6.1.1 for canine cancer therapy

et al. 2013

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“…All strains were derived from the GLV-1h68 oncolytic vaccinia virus strain (13). This strain was shown to be highly effective in numerous tumor models (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) and is currently being tested for safety and efficacy in several clinical trials in human cancer patients. For better understanding of the different strains listed in Table 1, we included details of the functional elements of the tet operator system in the names of the rVACV strains as follows.…”

Section: Resultsmentioning

confidence: 99%

Inducible Gene Expression in Tumors Colonized by Modified Oncolytic Vaccinia Virus Strains

Stritzker

Huppertz

Zhang

et al. 2014

J Virol

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Exogenous gene induction of therapeutic, diagnostic, and safety mechanisms could be a considerable improvement in oncolytic virotherapy. Here, we introduced a doxycycline-inducible promoter system (comprised of a tetracycline repressor, several promoter constructs, and a tet operator sequence) into oncolytic recombinant vaccinia viruses (rVACV), which were further characterized in detail. Experiments in cell cultures as well as in tumor-bearing mice were analyzed to determine the role of the inducible-system components. To accomplish this, we took advantage of the optical reporter construct, which resulted in the production of click-beetle luciferase as well as a red fluorescent protein. The results indicated that each of the system components could be used to optimize the induction rates and had an influence on the background expression levels. Depending on the given gene to be induced in rVACV-colonized tumors of patients, we discuss the doxycycline-inducible promoter system adjustment and further optimization. IMPORTANCEOncolytic virotherapy of cancer can greatly benefit from the expression of heterologous genes. It is reasonable that some of those heterologous gene products could have detrimental effects either on the cancer patient or on the oncolytic virus itself if they are expressed at the wrong time or if the expression levels are too high. Therefore, exogenous control of gene expression levels by administration of a nontoxic inducer will have positive effects on the safety as well as the therapeutic outcome of oncolytic virotherapy. In addition, it paves the way for the introduction of new therapeutic genes into the genome of oncolytic viruses that could not have been tested otherwise. Cancer remains one of the major health problems worldwide, and novel therapies are direly needed. Over the past decade, therapies which take advantage of tumor-colonizing microorganisms have gained more and more attention and become a significant field of research followed by ongoing clinical trials. Tumorcolonizing microorganisms include pathogenic, nonpathogenic, and even probiotic bacteria, as well as different virus strains. All of those microorganisms have in common the fact that they colonize and replicate in solid tumors and metastases to a much higher extent than in healthy tissues, resulting in tumor-to-organ ratios that by far exceed any other targeted therapies that are based on small molecules and therapeutic antibodies. This phenomenon of tumor-specific enrichment and amplification is either a consequence of rational genetic engineering or based on natural traits of those microorganisms or both. Whatever the basis for the tumorspecific replication is, tumor-colonizing microorganisms are now being used to (over)express heterologous therapeutic proteins within tumor tissues, thereby enhancing the therapeutic efficacy.Some of those therapeutic proteins can be toxic to the patient or even to the microorganism that produces the protein. Therefore, it would be beneficial to exogenously regulate their gene ...

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“…In previous studies it was shown that a recombinant VACV, GLV-1h68, leads to inhibition of tumor growth in different types of human cancers as well as canine mammary cancer (21)(22)(23)(24)(25)(26)(27)(28). In this study we wanted to improve the anti-tumor potency of this virus by constructing a derivative which carries a gene for a Walker A motif mutant (K237E) of Cdc6.…”

Section: Resultsmentioning

confidence: 99%

“…injection of GLV1h68 led to tumor regression of subcutaneous GI-101A human breast cancer xenografts. Furthermore, GLV-1h68 was used to successfully treat different types of human cancers as well as canine mammary cancers (22)(23)(24)(25)(26)(27)(28). In the present study we intended to further enhance the promising antitumor potential of GLV-1h68 without decreasing its safety.…”

Section: Discussionmentioning

confidence: 99%

“…Recently it was shown that a triple deletion of the F14.5L, J2R (encoding thymidine kinase) and A56R (encoding hemagglutinin) loci in the LIVP strain of VACV reduced toxicity and enhanced tumor targeting specificity compared with its parental LIVP strains (21). Treatment with this virus, GLV-1h68, leads to inhibition of tumor growth in human breast cancer (21), anaplastic thyroid carcinoma (22), malignant pleural mesothelioma xenografts (23), squamous cell carcinoma (24), pancreatic carcinomas (25), prostate carcinomas (26) as well as canine mammary adenoma (27) and carcinoma (28).…”

Section: Introductionmentioning

confidence: 99%

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Vaccinia virus GLV-1h237 carrying a Walker A motif mutation of mouse Cdc6 protein enhances human breast tumor therapy in mouse xenografts

Hofmann

Grummt²,

Szalay

2011

Int J Oncol

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Abstract.Recently it was shown that recombinant vaccinia virus GLV-1h68 is a promising tool for treating different type of cancers in animal models. The goal of the present study was to enhance the oncolytic potential of GLV-1h68 without decreasing its safety. A derivative of GLV-1h68 containing the gene for a Walker A motif mutant of the essential cell cycle protein Cdc6, GLV-1h237, was engineered. The characteristics of GLV-1h237 and its efficiency in treating human breast cancer GI-101A cells were compared with that of GLV-1h236 (carrying the wild-type gene for Cdc6), GLV-1h71 (a derivative of GLV-1h68) and GLV-1h68, respectively. RT-PCR and immunoblot analyses revealed that Cdc6 is efficiently overexpressed in GLV-1h237-infected GI-101A cells. GLV-1h237 was found to have higher replication efficiency and enhanced cytotoxity than GLV-1h68 in cell culture. In the GI-101A tumor xenograft animal model, GLV-1h237 turned out to be the most potent oncolytic virus strain investigated. A single i.v. injection of GLV-1h237 resulted in enhanced anti-tumor activity compared to GLV1h68 concomitant with a high tumor selectivity and a comparable safety profile. Thus, the strategy to combine oncolytic virotherapy with agents that interfere with host cell DNA synthesis is a promising approach for effective cancer therapy.

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Significant Growth Inhibition of Canine Mammary Carcinoma Xenografts following Treatment with Oncolytic Vaccinia Virus GLV-1h68

Cited by 30 publications

References 18 publications

Characterization and evaluation of a new oncolytic Vaccinia Virus strain LIVP6.1.1 for canine cancer therapy

Characterization and evaluation of a new oncolytic Vaccinia Virus strain LIVP6.1.1 for canine cancer therapy

Inducible Gene Expression in Tumors Colonized by Modified Oncolytic Vaccinia Virus Strains

Vaccinia virus GLV-1h237 carrying a Walker A motif mutation of mouse Cdc6 protein enhances human breast tumor therapy in mouse xenografts

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