Cytomegalovirus and brain tumor

Cobbs, Charles S.

doi:10.1097/cco.0000000000000005

Cited by 70 publications

(38 citation statements)

References 41 publications

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“…We report the induction of a severe hypersensitivity reaction in a patient with GBM enrolled on a clinical trial evaluating the use of autologous DCs pulsed with human cytomegalovirus (CMV) pp65 RNA and co-injected with recombinant GM-CSF (sargramostim) as an adjuvant. CMV antigens have been reported by several groups to be expressed in GBM tumors and we have demonstrated the relevance of CMV pp65 as an immunologic target in GBM tumors (10, 14–16). This is our first experience of a severe immunologic reaction in a patient receiving autologous DC vaccination, which occurred despite the patient being on continuous cycles of lymphodepletive and myelosuppressive TMZ.…”

Section: Introductionsupporting

confidence: 62%

Severe Adverse Immunologic Reaction in a Patient with Glioblastoma Receiving Autologous Dendritic Cell Vaccines Combined with GM-CSF and Dose-Intensified Temozolomide

Mitchell

Sayour

Reap

et al. 2015

Cancer Immunology Research

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Therapeutic vaccination of patients with cancer-targeting tumor-associated antigens is a promising strategy for the specific eradication of invasive malignancies with minimal toxicity to normal tissues. However, as increasingly potent modalities for stimulating immunologic responses are developed for clinical evaluation, the risk of inflammatory and autoimmune toxicities also may be exacerbated. In this report, we describe the induction of a severe (grade 3) immunologic reaction in a patient with newly diagnosed glioblastoma (GBM) receiving autologous RNA-pulsed dendritic cell (DC) vaccines admixed with GM-CSF and administered coordinately with cycles of dose-intensified temozolomide. Shortly after the eighth administration of the admixed intradermal vaccine, the patient experienced dizziness, flushing, conjunctivitis, headache, and the outbreak of a disseminated macular/papular rash and bilateral indurated injection sites. Immunologic workup of patient reactivity revealed sensitization to the GM-CSF component of the vaccine and the production of high levels of anti-GM-CSF autoantibodies during vaccination. Removal of GM-CSF from the DC vaccine allowed continued vaccination without incident. Despite the known lymphodepletive and immunosuppressive effects of temozolomide, these observations demonstrate the capacity for the generation of severe immunologic reactivity in patients with GBM receiving DC-based therapy during adjuvant dose-intensified temozolomide.

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Section: Introductionsupporting

confidence: 62%

Severe Adverse Immunologic Reaction in a Patient with Glioblastoma Receiving Autologous Dendritic Cell Vaccines Combined with GM-CSF and Dose-Intensified Temozolomide

Mitchell

Sayour

Reap

et al. 2015

Cancer Immunology Research

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“…Remarkably, a recent analysis of monozygotic twin pairs revealed that CMV infection was the primary factor driving nonheritable diversity in the immune system (2). Consistent with the dramatic impact of CMV on the host immune system, infection has been associated with multiple chronic inflammatory conditions, including high blood pressure, heart disease/atherosclerosis, cancer, and aging-related immunodeficiencies (3,4). Despite the clinical importance of human CMV (HCMV), there is currently no vaccine, and antiviral drugs are relatively toxic and cannot restrict viral persistence/latency.…”

mentioning

confidence: 92%

cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection

Lio

McDonald

Takahashi

et al. 2016

J Virol

111

103

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Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-IC ytomegalovirus (CMV) (human herpesvirus 5 [HHV-5], a betaherpesvirus) is one of the most common etiological agents of chronic viral infection in humans, with primary infection developing in the majority of people at relatively young ages and lasting for life (1). Although acute CMV infection is mostly asymptomatic in healthy individuals, debilitating and even fatal complications arise in those with weakened immune systems, including pregnant women, infants, transplant recipients, and HIV patients. Remarkably, a recent analysis of monozygotic twin pairs revealed that CMV infection was the primary factor driving nonheritable diversity in the immune system (2). Consistent with the dramatic impact of CMV on the host immune system, infection has been associated with multiple chronic inflammatory conditions, including high blood pressure, heart disease/atherosclerosis, cancer, and aging-related immunodeficiencies (3, 4). Despite the clinical importance of human CMV (HCMV), there is currently no vaccine, and antiviral drugs are relatively toxic and cannot restrict viral persistence/latency.Both mouse CMV (MCMV) and HCMV contain a linear double-stranded DNA (dsDNA) genome of ϳ230 kb encoding hundreds of viral open reading frames (ORFs) (5, 6). CMV harbors an arsenal of immunoregulatory genes that allow the virus to evade or dampen host immune defenses. However, despite these numerous strategies, the virus still induces significant levels of type I interferon (IFN-I) from infected cells both in vitro and in vivo. We have previously shown that MCMV induces a biphasic IFN-I response in vivo, with the first wave of IFN-I being completely independent of Toll-like receptor (TLR), Nalp3, and MAVS and emanating from virally infected stromal cells during the first 12 h (7,8). This "first burst" of IFN-I is followed by a later wave produced at 36 to 44 h by plasmacytoid dendritic cells (DCs) (pDCs) and conventional DCs (cDCs) in response to viral particles released from the infected stroma (7,(9)(10)(11). It is the first wave of IFN-I that is critical to limit viral spread in the peripheral organs (7), while the second pDC-derived wave is mostly dispensable for restricting MCMV replication levels (12). Despite our previous work showing that lymphotoxin (LT) signaling is required to promote an optimal first-phase IFN-I response to MCMV in vivo (7,8,11,13,14), the specific innate sensing pathway required for this initial production has remained uncharacterized, although

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“…More interestingly, HCMV also replicates in neural cells of glia, immature neurons, and neural progenitor/stem cells (NPCs), as well as in glioblastoma and neuroblastoma cell lines (5)(6)(7)(8)(9). Increasingly, observational studies have indicated that HCMV is associated with glioblastoma (10)(11)(12)(13), and recent reports find that this virus establishes persistent/latent infection in T98G glioblastoma cells (14,15). The brain and auditory system (16)(17)(18) are the end-organ sites where damage manifests as sensorineural hearing loss (SNHL), mental retardation, and developmental delays (3,(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

Liu

et al. 2015

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily manifesting as neurological disorders. HCMV infection alters expression of cellular microRNAs (miRs These results suggest that Cdc25a promotes HCMV replication and elevation of Cdc25a levels after HCMV infection are due in part to HCMV-mediated repression of miR-21. Thus, miR-21 is an intrinsic antiviral factor that is modulated by HCMV infection. This suggests a role for miR-21 downregulation in the neuropathogenesis of HCMV infection of the developing CNS. IMPORTANCEHuman cytomegalovirus (HCMV) is a ubiquitous pathogen and has very high prevalence among population, especially in China, and congenital HCMV infection is a major cause for birth defects. Elucidating virus-host interactions that govern HCMV replication in neuronal cells is critical to understanding the neuropathogenesis of birth defects resulting from congenital infection. In this study, we confirm that HCMV infection downregulates miR-21 but upregulates Cdc25a. Further determined the negative effects of cellular miRNA miR-21 on HCMV replication in neural progenitor/stem cells and U-251MG glioblastoma/astrocytoma cells. More importantly, our results provide the first evidence that miR-21 negatively regulates HCMV replication by targeting Cdc25a, a vital cell cycle regulator. We further found that viral gene products of IE1, pp71, and UL26 play roles in inhibiting miR-21 expression, which in turn causes increases in Cdc25a and benefits HCMV replication. Thus, miR-21 appears to be an intrinsic antiviral factor that represents a potential target for therapeutic intervention.

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Cytomegalovirus and brain tumor

Abstract: A more precise understanding of the role of HCMV infection in gliomagenesis and GBM pathogenesis could reveal novel therapeutic and preventive strategies.

Cited by 70 publications

References 41 publications

Severe Adverse Immunologic Reaction in a Patient with Glioblastoma Receiving Autologous Dendritic Cell Vaccines Combined with GM-CSF and Dose-Intensified Temozolomide

Severe Adverse Immunologic Reaction in a Patient with Glioblastoma Receiving Autologous Dendritic Cell Vaccines Combined with GM-CSF and Dose-Intensified Temozolomide

cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection

MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

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