Recombinant vaccinia virus GLV-1h68 is a promising oncolytic vector in the treatment of cholangiocarcinoma

Pugalenthi, Amudhan; Mojica, Kelly; Ady, Justin; Johnsen, Clark; Love, Damon; Chen, Nanhai G.; Aguilar, Richard J.; Szalay, Aladar A.; Fong, Yuman

doi:10.1038/cgt.2015.60

Cited by 22 publications

(18 citation statements)

References 37 publications

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“…This suggests that while the virus can disseminate to normal organs even after intra-tumoral injection, the virus is eventually cleared from those organs. Furthermore, a single injection of 10 3 PFUs of the virus, a dose 100-1000 folds lower than that commonly reported for oncolytic poxviruses [41][42][43][44], showed significant anti-tumor effects in both injected and un-injected distant tumors leading to significantly improved survival of mice.…”

Section: Discussionmentioning

confidence: 81%

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

et al. 2019

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Oncolytic viruses have shown excellent safety profiles in preclinical and clinical studies; however, in most cases therapeutic benefits have been modest. We have previously reported the generation of a chimeric poxvirus (CF33), with significantly improved oncolytic characteristics, through chimerization among different poxviruses. Here we report the sequence analysis of CF33 and oncolytic potential of a GFP-encoding CF33 virus (CF33-GFP) with a J2R deletion in lung cancer models. Replication of CF33-GFP and the resulting cytotoxicity were higher in cancer cell lines compared to a normal cell line, in vitro. After infection with virus, cancer cells expressed markers for immunogenic cell death in vitro. Furthermore, CF33-GFP was safe and exerted potent anti-tumor effects at a dose as low as 1000 plaque forming units in both virus-injected and un-injected distant tumors in A549 tumor xenograft model in mice. Likewise, in a syngeneic model of lung cancer in mice, the virus showed significant anti-tumor effect and was found to increase tumor infiltration by CD8+ T cells. Collectively, these data warrant further investigation of this novel chimeric poxvirus for its potential use as a cancer bio-therapeutic.

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Section: Discussionmentioning

confidence: 81%

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

et al. 2019

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“…129 In CCA, preclinical studies have attempted to identify viral vectors capable of tumour-cell selective replication and lysis. [130][131][132] An oncolytic adenovirus encoding immunostimulatory transgenes is currently being assessed in a clinical trial in solid tumours including CCA (NCT03225989; Table 3). There is an intriguing preclinical rationale behind the use of live, attenuated bacterial vectors, as they exhibit tropism for the hypoxic tumour microenvironment and the ability to stimulate innate and adaptive immune responses.…”

Section: Other Immunotherapeutic Strategiesmentioning

confidence: 99%

Immunobiology of cholangiocarcinoma

et al. 2019

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Cholangiocarcinoma (CCA) represents a heterogeneous group of epithelial tumours that are classified according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Although surgical resection and liver transplantation following neoadjuvant therapy are potentially curative options for a subset of patients with early-stage disease, the currently available medical therapies for CCA have limited efficacy. Immunotherapeutic strategies such as immune checkpoint blockade (ICB) harness the host immune system to unleash an effective and durable antitumour response in a subset of patients with a variety of malignancies. However, response to ICB monotherapy has been relatively disappointing in CCA. CCAs are desmoplastic tumours with an abundant tumour immune microenvironment (TIME) that contains immunosuppressive innate immune cells such as tumour-associated macrophages and myeloid-derived suppressor cells. A subset of CCAs may be classified as immune 'hot' tumours with a high density of CD8 + T cells and enhanced expression of immune checkpoint molecules. Immune 'hot' tumour types are associated with higher response rates to ICB. However, the suboptimal response rates to ICB monotherapy in human clinical trials of CCA imply that the preponderance of CCAs are immune 'cold' tumours with a non-T cell infiltrated TIME. An enhanced comprehension of the immunobiology of CCA, particularly the innate immune response to CCA, is essential in the effort to develop effective combination immunotherapeutic strategies that can target a larger subset of CCAs.

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“…A Lister-based strain of recombinant VACV called GLV-1h68 or GL-ONC1, combines a TK mutation with mutations in the viral hemagglutinin ( A56R ) and F14.5L genes ( 131 , 134 ). This virus demonstrated reduced virulence in nude mice ( 134 ), and oncolytic efficacy in several immune compromised animal models ( 135 – 138 ). Phase I/II trials in patients with head and neck cancer, lung cancer, peritoneal carcinomatosis, and additional solid tumors are currently underway [reviewed in Ref.…”

Section: Vaccinia Virusmentioning

confidence: 99%

Targeting Nucleotide Biosynthesis: A Strategy for Improving the Oncolytic Potential of DNA Viruses

2017

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The rapid growth of tumors depends upon elevated levels of dNTPs, and while dNTP concentrations are tightly regulated in normal cells, this control is often lost in transformed cells. This feature of cancer cells has been used to advantage to develop oncolytic DNA viruses. DNA viruses employ many different mechanisms to increase dNTP levels in infected cells, because the low concentration of dNTPs found in non-cycling cells can inhibit virus replication. By disrupting the virus-encoded gene(s) that normally promote dNTP biosynthesis, one can assemble oncolytic versions of these agents that replicate selectively in cancer cells. This review covers the pathways involved in dNTP production, how they are dysregulated in cancer cells, and the various approaches that have been used to exploit this biology to improve the tumor specificity of oncolytic viruses. In particular, we compare and contrast the ways that the different types of oncolytic virus candidates can directly modulate these processes. We limit our review to the large DNA viruses that naturally encode homologs of the cellular enzymes that catalyze dNTP biogenesis. Lastly, we consider how this knowledge might guide future development of oncolytic viruses.

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Recombinant vaccinia virus GLV-1h68 is a promising oncolytic vector in the treatment of cholangiocarcinoma

Cited by 22 publications

References 37 publications

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

Immunobiology of cholangiocarcinoma

Targeting Nucleotide Biosynthesis: A Strategy for Improving the Oncolytic Potential of DNA Viruses

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