Viral therapy of glioblastoma multiforme

Whitley, Richard J.; Markert, James M.

doi:10.1073/pnas.1310253110

Cited by 6 publications

(5 citation statements)

References 12 publications

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“…However, we note that the use of these degrading enzymes may cause serious complications such as hemorrhagic necrosis of brain, neurodegenerative diseases [26] , and optic glioma growth [27] . Treatment failures in glioblastoma are partially attributed to cellular heterogeneity [66] , [67] and local microenvironment [36] . We also found that the microenvironment plays a significant role in viral spread as demonstrated in Figure 4 , and this has implication for brain tissue with variable -diffusion coefficient .…”

Section: Discussionmentioning

confidence: 99%

Choindroitinase ABC I-Mediated Enhancement of Oncolytic Virus Spread and Anti Tumor Efficacy: A Mathematical Model

et al. 2014

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Oncolytic viruses are genetically engineered viruses that are designed to kill cancer cells while doing minimal damage to normal healthy tissue. After being injected into a tumor, they infect cancer cells, multiply inside them, and when a cancer cell is killed they move on to spread and infect other cancer cells. Chondroitinase ABC (Chase-ABC) is a bacterial enzyme that can remove a major glioma ECM component, chondroitin sulfate glycosoamino glycans from proteoglycans without any deleterious effects in vivo. It has been shown that Chase-ABC treatment is able to promote the spread of the viruses, increasing the efficacy of the viral treatment. In this paper we develop a mathematical model to investigate the effect of the Chase-ABC on the treatment of glioma by oncolytic viruses (OV). We show that the model's predictions agree with experimental results for a spherical glioma. We then use the model to test various treatment options in the heterogeneous microenvironment of the brain. The model predicts that separate injections of OV, one into the center of the tumor and another outside the tumor will result in better outcome than if the total injection is outside the tumor. In particular, the injection of the ECM-degrading enzyme (Chase-ABC) on the periphery of the main tumor core need to be administered in an optimal strategy in order to infect and eradicate the infiltrating glioma cells outside the tumor core in addition to proliferative cells in the bulk of tumor core. The model also predicts that the size of tumor satellites and distance between the primary tumor and multifocal/satellite lesions may be an important factor for the efficacy of the viral therapy with Chase treatment.

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Section: Discussionmentioning

confidence: 99%

Choindroitinase ABC I-Mediated Enhancement of Oncolytic Virus Spread and Anti Tumor Efficacy: A Mathematical Model

et al. 2014

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“…Based on the antitumor activity and antiangiogenic properties of IL-12, genes that express IL-12 have been inserted into the engineered oncolytic virus genome. In 2013, many studies reported that a genetically engineered oncolytic herpes simplex virus, when armed with the immunomodulatory cytokine interleukin 12, significantly enhanced the survival of tumor-bearing mice and effectively inhibited tumor growth [42][43][44][45][46] . Moreover, the safety and efficacy of the oncolytic virus were evaluated, and some strides were made in a clinical study.…”

Section: Oncolytic Viruses That Express Il-12mentioning

confidence: 99%

Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas

Zhang

Liu

2020

Cell Death Dis

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Glioblastoma (GBM) is an immunosuppressive, lethal brain tumor. Despite advances in molecular understanding and therapies, the clinical benefits have remained limited, and the life expectancy of patients with GBM has only been extended to~15 months. Currently, genetically modified oncolytic viruses (OV) that express immunomodulatory transgenes constitute a research hot spot in the field of glioma treatment. An oncolytic virus is designed to selectively target, infect, and replicate in tumor cells while sparing normal tissues. Moreover, many studies have shown therapeutic advantages, and recent clinical trials have demonstrated the safety and efficacy of their usage. However, the therapeutic efficacy of oncolytic viruses alone is limited, while oncolytic viruses expressing immunomodulatory transgenes are more potent inducers of immunity and enhance immune cell-mediated antitumor immune responses in GBM. An increasing number of basic studies on oncolytic viruses encoding immunomodulatory transgene therapy for malignant gliomas have yielded beneficial outcomes. Oncolytic viruses that are armed with immunomodulatory transgenes remain promising as a therapy against malignant gliomas and will undoubtedly provide new insights into possible clinical uses or strategies. In this review, we summarize the research advances related to oncolytic viruses that express immunomodulatory transgenes, as well as potential treatment pitfalls in patients with malignant gliomas. Facts Open questions 1. Can the immune system attack and engulf exogenous viruses? 2. Are glioma stem cells resistant to viral therapy? 3. Can the presence of nontumor cells such as tumor stroma cells impede the spread of oncolytic viruses? 4. In personalized medicine, should potential challenges be considered for the treatment of patients with malignant gliomas?

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“…IL12 is a potent immunostimulatory cytokine, capable of helping to break the tolerance to tumors and induce an immunotherapeutic response [ 72 ]. Its systemic administration is marred by toxicity, which can be overcome by loco-regional administration of the cytokine, e.g., by local administration via a viral vector encoding the IL12 gene [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. The rationale for choosing the US1-US2 intergenic locus as the insertion site was as follows.…”

Section: Resultsmentioning

confidence: 99%

HSV as A Platform for the Generation of Retargeted, Armed, and Reporter-Expressing Oncolytic Viruses

Menotti

Avitabile

Gatta

et al. 2018

Viruses

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Previously, we engineered oncolytic herpes simplex viruses (o-HSVs) retargeted to the HER2 (epidermal growth factor receptor 2) tumor cell specific receptor by the insertion of a single chain antibody (scFv) to HER2 in gD, gH, or gB. Here, the insertion of scFvs to three additional cancer targets—EGFR (epidermal growth factor receptor), EGFRvIII, and PSMA (prostate specific membrane antigen)—in gD Δ6–38 enabled the generation of specifically retargeted o-HSVs. Viable recombinants resulted from the insertion of an scFv in place of aa 6–38, but not in place of aa 61–218. Hence, only the gD N-terminus accepted all tested scFv inserts. Additionally, the insertion of mIL12 in the US1-US2 intergenic region of the HER2- or EGFRvIII-retargeted o-HSVs, and the further insertion of Gaussia Luciferase, gave rise to viable recombinants capable of secreting the cytokine and the reporter. Lastly, we engineered two known mutations in gB; they increased the ability of an HER2-retargeted recombinant to spread among murine cells. Altogether, current data show that the o-HSV carrying the aa 6–38 deletion in gD serves as a platform for the specific retargeting of o-HSV tropism to a number of human cancer targets, and the retargeted o-HSVs serve as simultaneous vectors for two molecules.

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Viral therapy of glioblastoma multiforme

Cited by 6 publications

References 12 publications

Choindroitinase ABC I-Mediated Enhancement of Oncolytic Virus Spread and Anti Tumor Efficacy: A Mathematical Model

Choindroitinase ABC I-Mediated Enhancement of Oncolytic Virus Spread and Anti Tumor Efficacy: A Mathematical Model

Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas

HSV as A Platform for the Generation of Retargeted, Armed, and Reporter-Expressing Oncolytic Viruses

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