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A recent report has suggested that glioma patients at the Karolinska University Hospital receiving 6 months of antiviral therapy as an add-on to standard radiation and temozolamide therapy exhibited marked increases in survival rates 95 , though the study design and mathematics used have been questioned 23 , Some other studies, but not all, have also shown improved outcomes in cancer patients on antiviral therapy 32 , These data may imply that the oncogenic effects of EBV—at least in B-cell lymphomas—are not affected by antiretroviral drugs.
For example, Zakaria et al. A corollary of this is the idea that stress resulting from co-infections may also be important in viral reactivation and oncogenesis. Although the low levels of EBV infections reported in gliomas, by themselves may not be sufficient, they likely require additional stress-causing risk factors, such as the co-presence of other oncoviruses, to influence oncogenesis or oncomodulation.
Tumor biology and cancer therapy – an evolving relationship
Vaccines against specific viruses may, therefore, offer a more targeted approach for association studies and clinical therapy [for review see Cohen ]. For example, an EBV vaccine has been tested in a phase I clinical trial on Chinese nasopharyngeal carcinoma patients to determine the safe and immunogenic dose In that study, it was concluded that the vaccine is both safe and immunogenic, thus paving the way for further clinical testing of the EBV vaccine that may be of clinical benefit in EBV-positive tumors including glioma patients.
The first prophylactic EBV vaccine based on virus-like particles VLPs that mimic the structure of the EBV virus, but lack its genome has also been reported to be effective in preclinical models and may represent a safer alternative. Finally, could it be that by looking for EBV and other herpes viruses like CMV, in gliomas we might have been focusing on the wrong viruses? Recent NGS sequencing data seems to suggest that most of the viruses especially CMV are completely absent from gliomas and many of the positive associations reported are likely artifactual as they may be rationally explained otherwise [e.
The reported low level presence of EBV does not completely rule it out from being associated with oncogenesis or oncomodulation in gliomas [indeed, it may not even need to be present to exert its effects as suggested by the study of Shumilov et al. Understanding the role of EBV and other oncoviruses in the etiology of gliomas, that generally have a poor prognosis, would likely open up new avenues for the treatment and management of these, often fatal, CNS tumors.
SA and A-EM conceived the review. SA and SV searched the literature. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Brain tumors. Am J Med Cancer statistics, CA Cancer J Clin — The pathobiology of glioma tumors.
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J Clin Med 6 Progress and problems in understanding and managing primary Epstein-Barr virus infections. The interaction between human papillomavirus and other viruses. Virus Res — Crit Rev Oncol Hematol — Epstein-Barr virus: 40 years on. Nat Rev Cancer — Murata T, Tsurumi T.
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Switching of EBV cycles between latent and lytic states. Rev Med Virol — Several other promising tumor vaccine strategies are also being used in clinical trials. Dendritic cells are professional antigen-presenting cells that can be primed with tumor antigen ex vivo 30 and then readministered to the patient, where they mediate T-cell activation. Numerous preclinical studies demonstrate that dendritic cells pulsed with glioma antigens can prime a cytotoxic lymphocyte response that is tumor specific; phase 1 and 2 clinical trials have been completed using dendritic cell strategies, with encouraging results.
Antibody-mediated drug delivery is a strategy designed with the dual purpose of increasing the local drug concentration while minimizing nonspecific systemic exposure. Monoclonal antibodies targeting glioma-specific structures have been coupled to radionuclides radioimmunoconjugates , exotoxins immunotoxins , or chemotherapeutic agents and are administrated locally. Antigens that are overexpressed in tumors relative to normal tissue are typically used, such as mutant EGFR, tenascin, and interleukin 4 or interleukin 13 receptors.
Gene therapy is based on the insertion or modification of genes into a cell to treat a disease. Gene delivery can be accomplished using a variety of vectors, from viruses to cell-based systems to synthetic vectors. In gliomas, viral vectors have been used to deliver suicide genes, proapoptotic genes, p53, cytokines, and caspases. Synthetic vector research has focused on the use of nanoparticles.
Liposomal vectors, for example, have been used to deliver therapeutic genes in the preclinical setting. A variety of other novel therapeutic approaches are also currently being researched, including the use of alternating electrical fields to disrupt cell division via a device called NovoTTFA NovoCure Ltd, Haifa, Israel , 34 currently in phase 3 trials, and the use of thermal lasers to denature tumor tissue. In conclusion, the survival of patients with GBM continues to improve, albeit more slowly than we would like. A wide variety of new techniques and agents are currently under study, alone and in combination.
Increased collective experience in their use and improved understanding of the complex biology of GBM may allow for more rational and effective therapy selection for patients, further extending survival in the years to come. Drafting of the manuscript : Clarke and Butowski. Critical revision of the manuscript for important intellectual content : Clarke, Butowski, and Chang.
Administrative, technical, and material support : Clarke and Butowski. Study supervision : Butowski and Chang. Additional Contributions: Ilona Garner, BS, provided editorial assistance in the preparation of this manuscript. All Rights Reserved. View Large Download. Accessed October 1, MGMT gene silencing and benefit from temozolomide in glioblastoma. Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results.
Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. Phase II trial of temozolomide plus O 6 -benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.
Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme [published correction appears in J Clin Oncol. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.
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