&lt;em&gt;Ex Vivo&lt;/em&gt; Infection of Live Tissue with Oncolytic Viruses

Diallo, Jean-Simon; Roy, Dominic G.; Abdelbary, Hesham; Silva, Naomi De; Bell, John C.

doi:10.3791/2854

Cited by 20 publications

(19 citation statements)

References 11 publications

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“…Together with our data for the E1B19K ‐deleted and for the TRAIL‐expressing viruses, we hypothesize that increased tumor cell killing by 5‐FC/5‐FU prodrug activation can be combined with these modifications for increased MSC‐mediated virus delivery. These considerations highlight that personalized virotherapy approaches are warranted, requiring the establishment of pretreatment tests for evaluation of tumor sensitivity to oncolytic viruses, or to virus‐drug combinations …”

Section: Discussionmentioning

confidence: 99%

Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells

et al. 2015

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Oncolytic viruses have demonstrated in pre-clinical and clinical studies safety and a unique pleiotropic activity profile of tumor destruction. Yet, their delivery suffers from virus inactivation by blood components and sequestration to healthy tissues. Therefore, mesenchymal stromal cells (MSCs) have been applied as carrier cells for shielded virus delivery to tumors after ex vivo infection with oncolytic viruses. However, infection and particle production by MSCs have remained unsatisfying. Here, we report engineered oncolytic adenoviruses (OAds) for improved virus production and delivery by MSCs. OAds are uniquely amenable to molecular engineering, which has facilitated improved tumor cell destruction. But for MSC-mediated regimens, OAd engineering needs to achieve efficient infection and replication in both MSCs and tumor cells. We show that an Ad5/3 chimeric OAd capsid, containing the adenovirus serotype 3 cell-binding domain, strongly increases the entry into human bone marrow-derived MSCs and into established and primary pancreatic cancer cells. Further, we reveal that OAd with engineered post-entry functions-by deletion of the anti-apoptotic viral gene E1B19K or expression of the death ligand TRAIL-markedly increased virus titers released from MSCs, while MSC migration was not hampered. Finally, these virus modifications, or viral expression of FCU1 for local 5-FC prodrug activation, improved tumor cell killing implementing complementary cytotoxicity profiles in a panel of pancreatic cancer cell cultures. Together, our study establishes post-entry modification of OAd replication for improving virus delivery by carrier cells and suggests a panel of optimized OAds for future clinical development in personalized treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells

et al. 2015

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“…Primary cancer and normal tissue specimens were obtained from consenting patients who underwent tumor resection. Sample processing has been described previously …”

Section: Methodsmentioning

confidence: 99%

Oncolytic Maraba Virus MG1 as a Treatment for Sarcoma

et al. 2017

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The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed. Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge. This study opens the door for the use of MG1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. Sarcomas are a rare and heterogeneous group of aggressive malignant solid tumors that, unlike carcinomas originating from epithelium, arise from a variety of mesenchymal tissues, such as muscle, connective tissue and bone. Sarcomas require a multimodal therapeutic approach that consists of multiagent chemotherapy, surgical resection and radiation. According to the National Cancer Institute, the overall 5-year survival rate for sarcoma patients is 50%, which drops to <20% for cases involving distant metastatic spread. As such, new treatment options for recurrent/metastatic sarcoma are direly needed.Immunotherapy could provide an alternative to chemotherapy yet there has been little focus on sarcoma in this field. This is likely due to sarcoma's heterogeneous nature and the relatively smaller number of patients it affects compared to carcinomas. However, immune checkpoint inhibitors, which have revolutionized the immunotherapy field and that have been very successful to date in melanoma (e.g., anti-CTLA4, anti-PD-1), have so far failed as monotherapies for sarcoma. 1Oncolytic viruses (OVs) constitute another form of an immunotherapy platform that has showed promising results in a broad range of cancers. OVs are engineered to take advantage of several hallmarks of cancer in order to preferentially replicate in tumor cells. Cancer-selective infection by OVs leads to cancer cell lysis and the parallel production of inflammatory cytokines, leading to innate and adaptive immune responses against both virus and tumor.2 OV treatment can lead to profound anti-tumor immune responses and cure...

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“…The viability of EGAS cores was assessed according to the modified method reported by Diallo et al, 2010 [28], using the PrestoBlue Cell Viability Reagent (Invitrogen, USA). The reagent contains a cell-permeable blue compound that is virtually nonfluorescent but is converted to highly red fluorescent compound by the viable cells.…”

Section: Methodsmentioning

confidence: 99%

Viability Reduction andRac1Gene Downregulation of HeterogeneousEx-VivoGlioma Acute Slice Infected by the Oncolytic Newcastle Disease Virus Strain V4UPM

Mustafa

Shamsuddin

Ideris

et al. 2013

BioMed Research International

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Oncolytic viruses have been extensively evaluated for anticancer therapy because this virus preferentially infects cancer cells without interfering with normal cells. Newcastle Disease Virus (NDV) is an avian virus and one of the intensively studied oncolytic viruses affecting many types of cancer including glioma. Nevertheless, the capability of NDV infection on heterogeneous glioma tissue in a cerebrospinal fluid atmosphere has never been reported. Recently, Rac1 is reported to be required for efficient NDV replication in human cancer cells and established a link between tumourigenesis and sensitivity to NDV. Rac1 is a member of the Rho GTPases involved in the regulation of the cell migration and cell-cycle progression. Rac1 knockdown leads to significant inhibition of viral replication. In this work, we demonstrated that NDV treatment led to significant reduction of tumour tissue viability of freshly isolated heterogeneous human brain tumour slice, known as an ex vivo glioma acute slice (EGAS). Analysis of gene expression indicated that reduced tissue viability was associated with downregulation of Rac1. However, the viability reduction was not persistent. We conclude that NDV treatment induced EGAS viability suppression, but subsequent downregulation of Rac1 gene may reduce the NDV replication and lead to regrowth of EGAS tissue.

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<em>Ex Vivo</em> Infection of Live Tissue with Oncolytic Viruses

Abstract: Oncolytic Viruses (OVs) are novel therapeutics that selectively replicate in and kill tumor cells

Cited by 20 publications

References 11 publications

Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells

Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells

Oncolytic Maraba Virus MG1 as a Treatment for Sarcoma

Viability Reduction andRac1Gene Downregulation of HeterogeneousEx-VivoGlioma Acute Slice Infected by the Oncolytic Newcastle Disease Virus Strain V4UPM

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