Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

Zhao, Xing; Chester, Cariad; Rajasekaran, Narendiran; He, Zhisong; Kohrt, Holbrook E.

doi:10.1158/1535-7163.mct-15-0695

Cited by 49 publications

(37 citation statements)

References 71 publications

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“…The unique susceptibility of cancer cells to reovirus infection is a result of defective immune response and aberrant cellular signaling that occur during tumorigenesis. With reovirus, tumor infective selectivity is thought to result from oncogenic Ras signaling and compromised antiviral defenses [ 20 ]. Ras activation enhances viral uncoating and disassembly, increases the generation of viral progeny with enhanced infectivity, and accelerates the release of progeny through enhanced apoptosis [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Cytokine-induced killer cell delivery enhances the antitumor activity of oncolytic reovirus

et al. 2017

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Oncolytic viruses (OV) have recently emerged as a promising therapeutic modality in cancer treatment. OV selectively infect and kill tumor cells, while sparing untransformed cells. The direct cytotoxic effects combined with the capacity to trigger an immune response make OV an appealing combination partner in the burgeoning field of cancer immunotherapy. One of the leading OV therapeutic candidates is the double-stranded RNA virus reovirus. In order to improve the oncolytic activity of reovirus and allow for systemic administration despite the prevalence of neutralizing antibodies, cytokine-induced killer (CIK) cells were explored as cell carriers for reovirus delivery. In this study, CIK cells were successfully loaded with reovirus ex vivo, and viral replication was limited in CIK cells. Confocal microscopy and flow cytometry demonstrated that CIK cells retained reovirus on the surface. Moreover, CIK cells could promote reovirus infection of tumor cells in the presence of neutralizing antibodies; meanwhile, cytotoxicity of CIK cells was increased after loading with reovirus. These findings support further investigation of reovirus and CIK combination for antitumor therapy.

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Section: Discussionmentioning

confidence: 99%

Cytokine-induced killer cell delivery enhances the antitumor activity of oncolytic reovirus

et al. 2017

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“…This leads to enhanced virus release and spread from the infected cells 3,4 . These observations led to the initiation of a series of clinical trials in which the wild-type reovirus T3D was administered to patients as viral anti-cancer agent 5 .…”

Section: Introductionmentioning

confidence: 99%

Characterization of a replicating expanded tropism oncolytic reovirus carrying the adenovirus E4orf4 gene

et al. 2018

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While the mammalian orthoreovirus type 3 dearing (reovirus T3D) infects many different tumour cells, various cell lines resist the induction of reovirus-mediated cell death. In an effort to increase the oncolytic potency, we introduced transgenes into the S1 segment of reovirus T3D. The adenovirus E4orf4 gene was selected as transgene since the encoded E4orf4 protein induces cell death in transformed cells. The induction of cell death by E4orf4 depends in part on its binding to phosphatase 2A (PP2A). In addition to the S1-E4orf4 reovirus, two other reoviruses were employed in our studies. The reovirus rS1-RFA encodes an E4orf4 double-mutant protein that cannot interact with PP2A and the rS1-iLOV virus encoding the fluorescent marker iLOV as a reporter. The replacement of the codons for the junction adhesion molecule-A (JAM-A) binding head domain of the truncated spike protein blocks the entry of these recombinant viruses via the reovirus receptor JAM-A. Instead these viruses rely on internalization via binding to sialic acids on the cell surface. This expands their tropism and allows infection of JAM-A-deficient tumour cells. Here we not only demonstrate the feasibility of this approach but also established that the cytolytic activity of these recombinant viruses is largely transgene independent.

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“…Mammalian orthoreovirus, henceforth referred to as reovirus, is broadly studied as an anti-cancer agent both as a monotherapy and in combination with existing therapies [ 1 ]. It has the natural preference to replicate in and lyze tumor cells, while an antiviral response in normal cells hinders virus replication and cytolysis.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic Reovirus Infection Is Facilitated by the Autophagic Machinery

Kemp

Dautzenberg

Limpens

et al. 2017

Viruses

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Mammalian reovirus is a double-stranded RNA virus that selectively infects and lyses transformed cells, making it an attractive oncolytic agent. Despite clinical evidence for anti-tumor activity, its efficacy as a stand-alone therapy remains to be improved. The success of future trials can be greatly influenced by the identification and the regulation of the cellular pathways that are important for reovirus replication and oncolysis. Here, we demonstrate that reovirus induces autophagy in several cell lines, evident from the formation of Atg5-Atg12 complexes, microtubule-associated protein 1 light chain 3 (LC3) lipidation, p62 degradation, the appearance of acidic vesicular organelles, and LC3 puncta. Furthermore, in electron microscopic images of reovirus-infected cells, autophagosomes were observed without evident association with viral factories. Using UV-inactivated reovirus, we demonstrate that a productive reovirus infection facilitates the induction of autophagy. Importantly, knock-out cell lines for specific autophagy-related genes revealed that the expression of Atg3 and Atg5 but not Atg13 facilitates reovirus replication. These findings highlight a central and Atg13-independent role for the autophagy machinery in facilitating reovirus infection and contribute to a better understanding of reovirus-host interactions.

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Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

Cited by 49 publications

References 71 publications

Cytokine-induced killer cell delivery enhances the antitumor activity of oncolytic reovirus

Cytokine-induced killer cell delivery enhances the antitumor activity of oncolytic reovirus

Characterization of a replicating expanded tropism oncolytic reovirus carrying the adenovirus E4orf4 gene

Oncolytic Reovirus Infection Is Facilitated by the Autophagic Machinery

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