Abstract
Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year. Over the last decade, investigators have reliably identified human cytomegalovirus (HCMV) proteins, nucleic acids, and virions in most high-grade gliomas, including glioblastoma (GBM). This discovery is significant because HCMV gene products can be targeted by immune-based therapies. In this review, we describe the current level of understanding regarding the presence and role in pathogenesis of HCMV in GBM. We describe our success detecting and expanding HCMV-specific cytotoxic T lymphocytes to kill GBM cells and explain how these cells can be used as a platform for enhanced cellular therapies. We discuss alternative approaches that capitalize on HCMV infection to treat patients with HCMV-positive tumors. Adoptive cellular therapy for HCMV-positive GBM has been tried in a small number of patients with some benefit, but we reason why, to date, these approaches generally fail to generate long-term remission or cure. We conjecture how cellular therapy for GBM can be improved and describe the barriers that must be overcome to cure these patients.
Highlights
Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year [1]
Investigators have reliably identified human cytomegalovirus (HCMV) proteins, nucleic acids, and virions in most high-grade gliomas. This discovery is significant because HCMV gene products can be targeted by immune-based therapies, offering a new therapeutic approach for patients with HCMV-positive GBM
We found that a high proportion of GBMs in children contain intermediate-early 1 (IE1) and pp65, the rate of HCMV-protein expression in pediatric GBM was lower than reported values for adults (Corder, Ahmed et al, in review)
Summary
Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year [1]. Those using cytotoxic T cells (CTL), have been effective in treating disseminated viral infections [2] and Epstein-Barr Virus-associated malignancies [3, 4], successes in treating patients with solid tumors by targeting tumor-associated antigens (TAA) have been more tempered. Investigators have reliably identified human cytomegalovirus (HCMV) proteins, nucleic acids, and virions in most high-grade gliomas. This discovery is significant because HCMV gene products can be targeted by immune-based therapies, offering a new therapeutic approach for patients with HCMV-positive GBM. We discuss other important immune-based techniques for killing GBM and describe alternative approaches that capitalize on HCMV infection in a subset of GBM patients. The thickness of paraffin block sections is important for optimizing detection of HCMV proteins, and 6 μm is an accepted standard for this process [6]
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