EBV-associated T/NK-cell lymphoproliferative disease (T/NK-LPD) is defined as

Tissue hypoxia and necrosis represent pathophysiological and histological hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently >50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness, and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

To enhance the oncolytic activity of herpes simplex viruses (HSVs) control of immune-suppression and immune-resistance by cancer cells is important. Myeloid-derived suppressor cells (MDSCs), which interfere with tumor-suppressive environments, are inhibited by gemcitabine (GEM) treatment. We investigated the oncolytic activity and systemic antitumor immunity induced by oncolytic HSVs in combination with GEM treatment. A mouse model with subcutaneous tumors on both sides of the lateral flanks was used. A highly attenuated HSV type 1, strain HF10, was inoculated into one side of each tumor three times following intraperitoneal injection of GEM. Histopathological changes and IFN-c secretion of the tumor and leukocytes in the spleen were analyzed. These treatments were repeated to enhance oncolytic activity. HF10 inoculation reduced tumor growth only on the HF10-treated side. HF10 inoculation following GEM treatment resulted in greater reduction of tumor growth on the HF10-treated tumor; furthermore, reduction of tumors on the contralateral untreated side was also observed. Necrosis of the tumor was observed in areas where HSV-infected cells were detected. F4/80 1 macrophages around the tumor were eliminated, and CD4 1 T and CD8 1 T cells increased in the spleen. A single injection of GEM decreased CD11b 1 /Gr-1 1 MDSCs while retaining CD4 1 T cells and CD8 1 T cells. Repetition of this treatment regimen resulted in even greater reduction of tumor growth on both sides and complete rejection in some of the mice. Intratumoral injection of oncolytic HSVs following GEM injection reduced MDSCs. Repeated treatment with oncolytic HSVs following GEM resulted in enhanced oncolytic activity.Genetically altered, replication-competent viruses have been developed for cancer therapy, 1 as well as for gene-delivery vectors 2 and vaccine vectors. 3 The use of viruses that selectively replicate in and kill tumor cells is called oncolytic virotherapy. At present, oncolytic virotherapy is a promising anticancer therapy, as cancer-cell specific viral replication can boost therapeutic efficacy. 4,5 Herpes simplex virus (HSV) has many advantages over other viruses for oncolytic virotherapy.First, it has a broad host range and high efficiency of infection. Second, HSV can be engineered to deliver therapeutic transgenes, since it has a large genomic capacity. Furthermore, HSV can be controlled by antiherpetic drugs, such as acyclovir.HF10 is a spontaneously occurring, highly attenuated virus isolated from the HSV-1 strain HF in our laboratory. 6,7 We have been exploring the potential use of HF10 as an oncolytic agent using various tumor models. [7][8][9][10][11][12][13][14][15] In a subcutaneous tumor model of murine colorectal cancer that uses CT26 cells, oncolytic activity of HF10 was detected; however, its antitumor effect was limited. 10 In CT26 cells, tumor-associated macrophages (TAMs), which prompt tumor growth, were reported to accumulate around the tumor mass. 16 Control of immune-suppression and immune-resistance by cancer cells ...

Hearing loss and vestibular dysfunction were observed in all mice after inoculation of HSV type 1 or 2. In the cochlear duct, columnar epithelial cells in the stria vascularis were infected with HSV, but only a portion of the infected cells underwent apoptosis. In contrast, many uninfected cells in the spiral organ of Corti were apoptotic. Vestibular dysfunction was observed when vestibular ganglion cells were largely infected, but not apoptotic. These findings recapitulate sudden deafness and vestibular neuritis described in patients.