Armed replicating adenoviruses for cancer virotherapy

Cody, James J.; Douglas, Joanne T.

doi:10.1038/cgt.2009.3

Cited by 69 publications

(57 citation statements)

References 152 publications

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“…Human adenoviruses, such as HAdV-5, have been extensively investigated for vectored vaccine and gene therapy due to their aptitude for inducing potent innate and adaptive immune responses (10,13,28). However, the use of HAdV-based vectors is Target and reference gene expression levels were quantified by RT-qPCR, and levels are presented relative to ␤-actin expression and normalized to a calibrator.…”

Section: Discussionmentioning

confidence: 99%

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Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

Deng

Sharif

Nagy

2013

Clin Vaccine Immunol

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Fowl adenoviruses (FAdVs) are a potential alternative to human adenovirus-based vaccine vectors. Our previous studies demonstrated that a 2.4-kb region at the left end of the FAdV-9 genome is nonessential for virus replication and is suitable for the insertion or replacement of transgenes. Our in vivo study showed that the virus FAdV-9⌬4, lacking six open reading frames (ORFs) at the left end of its genome, replicates less efficiently than wild-type FAdV-9 (wtFAdV-9) in chickens that were infected intramuscularly. However, the fecal-oral route is the natural route of FAdV infection, and the oral administration of a vaccine confers some advantages compared to administration through other routes, especially when developing an adenovirus as a vaccine vector. Therefore, we sought to investigate the effects of FAdV-9 in orally inoculated chickens. In the present study, we orally inoculated specific-pathogen-free (SPF) chickens with FAdV-9 and FAdV-9⌬4 and assessed virus shedding, antibody response, and viral genome copy number and cytokine gene expression in tissues. Our data showed that FAdV-9⌬4 replicated less efficiently than did wtFAdV-9, as evidenced by reduced virus shedding in feces, lower viral genome copy number in tissues, and lower antibody response, which are consistent with the results of the intramuscular route of immunization. Furthermore, we found that both wtFAdV-9 and FAdV-9⌬4 upregulated the mRNA expression of alpha interferon (IFN-␣), IFN-␥, and interleukin-12 (IL-12). In addition, there was a trend toward downregulation of IL-10 gene expression caused by both viruses. These findings indicate that one or more of the six deleted ORFs contribute to modulating the host response against virus infection as well as virus replication in vivo.

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Section: Discussionmentioning

confidence: 99%

“…Human adenoviruses (HAdVs) and other mammalian adenoviruses are used both as oncolytic viruses (10)(11)(12) and vaccine vectors (13,14). FAdVs are also suitable vectors; for example, FAdV-1-and FAdV-8-based recombinant viruses have induced protective immune responses against infectious bursal disease virus and infectious bronchitis virus, respectively (15,16).…”

mentioning

confidence: 99%

Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

Deng

Sharif

Nagy

2013

Clin Vaccine Immunol

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“…These include engineering viral genes to increase virus release and spread, 4 combining the virus with other standard or experimental treatments, 5 --8 or arming adenoviruses with therapeutic transgenes. 9 The insertion of transgenes in the viruses can overcome some of their limitations and/or provide additional therapeutic benefits, separate to the properties of the virus itself. In this regard, enzymes like relaxin or hyaluronidase have been used to disrupt the extracellular matrix and enhance adenovirus spread; 10 --12 immune response-modifying genes have been used to stimulate an immune response against the tumor, 13 --16 and prodrug-activating enzymes with bystander effect have been used to increase the cytotoxicity of oncolytic adenoviruses.…”

Section: Introductionmentioning

confidence: 99%

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

et al. 2011

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The limitations of the current oncolytic adenoviruses for cancer therapy include insufficient potency and poor distribution of the virus throughout the tumor mass. To address these problems, we generated an oncolytic adenovirus expressing the hyperfusogenic form of the gibbon-ape leukemia virus (GALV) envelope glycoprotein under the control of the adenovirus major late promoter. The oncolytic properties of the new fusogenic adenovirus, ICOVIR16, were analyzed both in vitro and in vivo, and compared with that of its non-fusogenic counterpart, ICOVIR15. Our results indicate that GALV expression by ICOVIR16 induced extensive syncytia formation and enhanced tumor cell killing in a variety of tumor cell types. When injected intratumorally or intravenously into mice with large pre-established melanoma or pancreatic tumors, ICOVIR16 rapidly reduced tumor burden, and in some cases, resulted in complete eradication of the tumors. Importantly, GALV expression induced tumor cell fusion in vivo and enhanced the spreading of the virus throughout the tumor. Taken together, these results indicate that GALV expression can improve the antitumoral potency of an oncolytic adenovirus and suggest that ICOVIR16 is a promising candidate for clinical evaluation in patients with cancer.

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“…42 In addition to their inherent cytotoxicity, oncolytic viruses can also be used as vectors for gene delivery. 40,41,43,44 contributing to the tumor microenvironment through promoting angiogenesis, stroma formation, and immunosuppressive effects. NSCs were the first stem/progenitor cells tested for homing to GBM tumors and are currently in clinical trial for GBM (Table II).…”

Section: Gene Delivery Vehicles For Glioblastomamentioning

confidence: 99%

Current Status of Gene Therapy for Brain Tumors∗

Ning

Rabkin

2015

Translating Gene Therapy to the Clinic

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Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replicationcompetent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.Treating malignant gliomas, of which glioblastoma (GBM) is the most common and least curable, remains a daunting challenge even after substantial efforts to develop alternative therapies. The current standard of care is maximal surgical resection followed by radiation and temozolomide chemotherapy; however, the median survival still remains less than 15 months. 1,2 This poor survival is due to the aggressive and invasive nature of the tumor cells, resistance to treatment, and the challenges of delivering therapeutics into the brain. 3 GBM is thought to be derived from a small population of glioblastoma stem cells (GSCs), so-called because of their stem cell-like properties of self-renewal and multilineage differentiation while being highly tumorigenic. [4][5][6] GSCs have become an important model for studying GBM because their xenografts mimic the heterogeneous histopathology of the patient's tumor from which they were derived 7,8 and they remain genotypically similar to the patient's tumor, in contrast to serum-cultured cell lines. 9 These cells have provided insights into the origin of tumor-initiating cells and new targets for therapy. Other GBM animal models include established glioma cell lines (human and rodent) implanted intracranially into immunodeficient or immunocompetent animals, and genetically engineered mice that spontaneously develop brain tumors or are induced with viral vectors. 10 GENE DELIVERY VEHICLES FOR GLIOBLASTOMAMost gene therapies for GBM use biologic vectors such as viruses or cells. Replicationdefective or non-repli...

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Armed replicating adenoviruses for cancer virotherapy

Cited by 69 publications

References 152 publications

Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

Current Status of Gene Therapy for Brain Tumors∗

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