A5102803729- Virus-based gene therapy research
- Herpesvirus Infections and Treatments
- Viral Infectious Diseases and Gene Expression in Insects
- Cytomegalovirus and herpesvirus research
- RNA Interference and Gene Delivery
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Cancer Research and Treatments
- Immune cells in cancer
- Neuroinflammation and Neurodegeneration Mechanisms
- Glioma Diagnosis and Treatment
- interferon and immune responses
- CRISPR and Genetic Engineering
- Neuroblastoma Research and Treatments
- Animal Virus Infections Studies
- HIV Research and Treatment
- Immunotherapy and Immune Responses
- Glycosylation and Glycoproteins Research
- Vector-Borne Animal Diseases
- Mosquito-borne diseases and control
- Cancer Genomics and Diagnostics
- Bladder and Urothelial Cancer Treatments
- MicroRNA in disease regulation
- Cancer Immunotherapy and Biomarkers
- Toxin Mechanisms and Immunotoxins
University of Pittsburgh
2006-2019
Neurological Surgery
2006-2019
UPMC Hillman Cancer Center
2015-2019
Oncor (United States)
2018
University of Pittsburgh Medical Center
2016
Carnegie Mellon University
2016
Northwestern University
2016
University of California, San Francisco
2016
Memorial Sloan Kettering Cancer Center
2016
University of Ferrara
2006-2014
Abstract Oncolytic viral therapy provides a promising approach to treat certain human malignancies. These vectors improve on replication-deficient by increasing the load within tumors through preferential replication tumor cells. However, inability efficiently propagate throughout entire and infect cells distant from injection site has limited capacity of oncolytic viruses achieve consistent therapeutic responses. Here we show that spread herpes simplex virus (HSV) vector MGH2 melanoma Mu89...
Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse is unknown. Gain-of-function mutations isocitrate dehydrogenases (IDH1 and IDH2) promote glioma formation through epigenetic reprogramming of a number genes, including immune-related genes. Here, we identify dysregulation natural killer (NK) cell ligand genes as significant contributors to immune escape glioma. We analyzed the database Cancer Genome Atlas gene expression...
Immunotherapy of cancer is now an essential pillar treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration new strategies incorporating agents in clinical practice. Immunotherapies perturb complex system interactions among genomically unstable cells, diverse cells within the microenvironment including systemic adaptive innate cells. The drive to develop increasingly effective immunotherapy regimens tempered by risk...
Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient replication tumor cells. This disappointing outcome can be attributed part to attenuating mutations engineered into these viruses prevent normal Alternatively, retargeting of fully replication-competent HSV tumor-associated receptors the potential achieve specificity without...
Glioblastoma multiforme (GBM) is an aggressive brain cancer for which there no effective treatment. Oncolytic HSV vectors (oHSVs) are attenuated lytic viruses that have shown promise in the treatment of human GBM models animals, but their efficacy early phase patient trials has been limited. Instead attenuating virus with mutations virulence genes, we engineered four copies recognition sequence miR-124 into 3'UTR essential ICP4 gene to protect healthy tissue against replication; expressed...
Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear provoke a robust immune response against tumor. As OVs enter tumor cells, intrinsic host defenses have potential hinder replication and spread within mass. In report, we show histone deacetylase 6 (HDAC6) cells appears alter trafficking post-entry from nucleus toward lysosomes. glioma...
The use of mutant strains oncolytic herpes simplex virus (oHSV) in early-phase human clinical trials for the treatment glioblastoma multiforme (GBM) has proven safe, but limited efficacy suggests that more potent vector designs are required effective GBM therapy. Inadequate performance may derive from poor intratumoral replication and spread to uninfected cells. Vector be impaired by mutagenesis strategies achieve safety, hampered entrapment tumor-specific extracellular matrix (ECM) is...
ABSTRACT Herpes simplex virus (HSV) entry into cells is triggered by the binding of envelope glycoprotein D (gD) to a specific receptor, such as nectin-1 or herpesvirus mediator (HVEM), resulting in activation fusion effectors gB and gH penetration. Here we report identification hyperactive allele, D285N/A549T, selected repeat passage gD mutant defective for through that express gD-binding-impaired nectin-1. The allele wild-type background enabled use other nectins receptors. In addition,...
Multiple studies have indicated that in addition to direct oncolysis, virotherapy promotes an antitumor cytotoxic T cell response important for efficacy. To study this phenomenon further, we tested three syngeneic murine sarcoma models displayed varied degrees of permissiveness oncolytic herpes simplex virus replication and cytotoxicity vitro, with the most permissive being comparable some human tumor lines. The vivo effect ranged from no or modest complete regression protection rechallenge....
Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex (oHSVs) a genetically engineered mouse model isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common malignant primary brain adults. Our recapitulates genomics, diffuse infiltrative growth pattern, extensive macrophage-dominant...
Both initial infection and cell-to-cell spread by herpes simplex virus type 1 (HSV-1) require the interaction of viral glycoprotein D (gD) with an entry receptor on cell surface. The two major HSV receptors, herpesvirus mediator (HVEM) nectin-1, mediate independently but are coexpressed a variety cells. To determine if both receptors active in these instances, we have established mutant viruses that selectively impaired for recognition one or other receptor. In plaque assays, showed...
Both entry and cell-to-cell spread of herpes simplex virus (HSV) involve a cascade cooperative interactions among the essential glycoproteins D, B, H/L (gD, gB, gH/gL, respectively) initiated by binding gD to cognate HSV receptor. We previously reported that variant (D285N/A549T) glycoprotein B (gB:NT) enabled primary into cells were devoid typical receptors. Here, we compared activities gB:NT with those newly selected H (gH:KV) frequently coselected gB (gB:S668N). In combination, gH:KV...
Successful oncolytic virus treatment of malignant glioblastoma multiforme depends on widespread tumor-specific lytic replication and escape from mitigating innate immune responses to infection. Here we characterize a new HSV vector, JD0G, that is deleted for ICP0 the joint sequences separating unique long short elements viral genome. We observed JD0G was enhanced in certain cell lines compared HEL cells, suggesting vector backbone may be useful glioblastoma. The response infection can...
<h3>Background</h3> CG0070, an oncolytic vaccine available as intravesical therapy, is a serotype 5 adenovirus engineered to express GM-CSF and replicate in tumor cells with mutated or deficient RB (which results increased of the transcription factor E2F). The CG0070 mechanism action includes direct cell lysis conjunction immunogenic death which enhanced presence GM-CSF. In initial phase 1 study well subsequent 2 study, overall CR rate ~62% at 12 months (m) 29% have been observed patients...