The mechanisms of genetically modified vaccinia viruses for the treatment of cancer

Jefferson, Artrish; Cadet, Valerie E.; Hielscher, Abigail

doi:10.1016/j.critrevonc.2015.04.001

Cited by 28 publications

(15 citation statements)

References 65 publications

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“…In addition, oncolytic viruses can improve tumor regression when combined with radiation and chemotherapy (19)(20)(21)(22). Replication of viruses in tumor cells can also elicit a beneficial immune response, representing a novel avenue of oncolysis (25). Oncolytic viruses can also be engineered to stimulate antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

Mell

Brumund

Daniels³

et al. 2017

Clinical Cancer Research

108

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Purpose: Preclinical models have shown that the effectiveness of GL-ONC1, a modified oncolytic vaccinia virus, is enhanced by radiation and chemotherapy. The purpose of this study was to determine the safety of GL-ONC1 when delivered intravenously with chemoradiotherapy to patients with primary, nonmetastatic head and neck cancer.Experimental Design: Patients with locoregionally advanced unresected, nonmetastatic carcinoma of the head/neck, excluding stage III-IVA p16-positive oropharyngeal cancers, were treated with escalating doses and cycles of intravenous GL-ONC1, along with radiotherapy and chemotherapy. The primary aims were to define the MTD and dose-limiting toxicities, and to recommend a dose for phase II trials.Results: Between May 2012 and December 2014, 19 patients were enrolled. The most frequent adverse reactions included grade 1-2 rigors, fever, fatigue, and rash. Grade 3 adverse reactions included hypotension, mucositis, nausea, and vomiting. In 2 patients, the rash was confirmed as viral in origin by fluorescence imaging and viral plaque assay. In 4 patients, viral presence in tumor was confirmed on midtreatment biopsy by quantitative PCR. In 1 patient, live virus was confirmed in a tongue tumor 7 days after receiving the first dose of virus. The MTD was not reached. With median follow-up of 30 months, 1-year (2-year) progression-free survival and overall survival were 74.4% (64.1%) and 84.6% (69.2%), respectively.Conclusions: Delivery of GL-ONC1 is safe and feasible in patients with locoregionally advanced head/neck cancer undergoing standard chemoradiotherapy. A phase II study is warranted to further investigate this novel treatment strategy.

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Section: Discussionmentioning

confidence: 99%

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

Mell

Brumund

Daniels³

et al. 2017

Clinical Cancer Research

108

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“…Use of vaccinia viruses has received increased interest as strategies to engineer more potent oncolytic forms of vaccinia viruses has not only resulted in greater tumor specificity but have been shown to be an efficient means by which to lyse tumor cells 49. Recently, a genetically engineered vaccinia virus was reported to target both malignant ovarian cancer cells in addition to the fibroblasts in the tumor stroma 50.…”

Section: Future Outlook: Potential Strategies For Targeting Fibronectinmentioning

confidence: 99%

Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting

Wang¹,

Hielscher²

2017

J. Cancer

Self Cite

150

134

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Fibronectin is a matrix glycoprotein which has not only been found to be over-expressed in several cancers, but has been shown to participate in several steps of tumorigenesis. The purpose of this review is to illustrate how aberrant fibronectin expression influences tumor growth, invasion, metastasis and therapy resistance. In particular, this review will focus on the interactions between cell receptor ligands and fibronectin and how this interaction influences downstream signaling events that aid tumor progression. This review will further discuss the possible implications of therapeutic drugs directed against fibronectin and/or cellular interactions with fibronectin and will additionally discuss novel approaches by which to limit intra- and extra-tumoral fibronectin expression and the cellular events which lead to aberrant fibronectin expression. It is anticipated that these studies will set a basis for future research that will not only aid understanding of fibronectin and its prognostic significance, but will further elucidate novel targets for therapeutics.

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“…Genetically modified VACVs are promising agents for the treatment of various types of cancer and could be particularly useful for cancers with drug resistance syndrome [33, 34]. Indeed the chemoresistant tumors are the case when the effect of the antitumor activity of oncolytic viruses outbalances the effect of their general toxicity.…”

Section: Discussionmentioning

confidence: 99%

Engineering of double recombinant vaccinia virus with enhanced oncolytic potential for solid tumor virotherapy

et al. 2016

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Vaccinia virus (VACV) oncolytic therapy has been successful in a number of tumor models. In this study our goal was to generate a double recombinant vaccinia virus (VV-GMCSF-Lact) with enhanced antitumor activity that expresses exogenous proteins: the antitumor protein lactaptin and human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lactaptin has previously been demonstrated to act as a tumor suppressor in mouse hepatoma as well as MDA-MB-231 human adenocarcinoma cells grafted into SCID mice. VV-GMCSF-Lact was engineered from Lister strain (L-IVP) vaccinia virus and has deletions of the viral thymidine kinase and vaccinia growth factor genes. Cell culture experiments revealed that engineered VV-GMCSF-Lact induced the death of cultured cancer cells more efficiently than recombinant VACV coding only GM-CSF (VV-GMCSF-dGF). Normal human MCF-10A cells were resistant to both recombinants up to 10 PFU/cell. The selectivity index for breast cancer cells measured in pair cultures MCF-7/MCF-10A was 200 for recombinant VV-GMCSF-Lact coding lactaptin and 100 for VV-GMCSF-dGF. Using flow cytometry we demonstrated that both recombinants induced apoptosis in treated cells but that the rate in the cells with active caspase −3 and −7 was higher after treatment with VV-GMCSF-Lact than with VV-GMCSF-dGF. Tumor growth inhibition and survival outcomes after VV-GMCSF-Lact treatment were estimated using immunodeficient and immunocompetent mice models. We observed that VV-GMCSF-Lact efficiently delays the growth of sensitive and chemoresistant tumors. These results demonstrate that recombinant VACVs coding an apoptosis-inducing protein have good therapeutic potential against chemoresistant tumors. Our data will also stimulate further investigation of coding lactaptin double recombinant VACV in clinical settings.

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The mechanisms of genetically modified vaccinia viruses for the treatment of cancer

Cited by 28 publications

References 65 publications

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting

Engineering of double recombinant vaccinia virus with enhanced oncolytic potential for solid tumor virotherapy

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