Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation

Endo, Yoshikatsu; Sakai, Ryo; Ouchi, Masaaki; Onimatsu, Hideki; Hioki, Mika; Kagawa, Shunsuke; Uno, Futoshi; Watanabe, Yuichi; Urata, Yasuo; Tanaka, Noriaki; Fujiwara, Toshiyoshi

doi:10.1038/sj.onc.1210884

Cited by 80 publications

(81 citation statements)

References 15 publications

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“…Telomelysin has been shown to selectively kill human cancer cells (8)(9)(10)(11). In infected human tumor cells in vitro, OBP-301 replication produces the endogenous danger-signaling molecule uric acid, which in turn stimulates dendritic cells to produce interferon Á (IFNÁ) and interleukin (IL)-12 (12). In vivo, OBP-301 induces CD4 + and CD8 + T cells following production of INFÁ (13).…”

Section: Introductionmentioning

confidence: 99%

Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

et al. 2009

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Abstract. We previously reported that telomerase-specific replication-component adenovirous, Telomelysin has cytotoxic activity to the YCUT892, KCCT873, KCCT891, KCCL871, YCUM862, HN12, and KCCOR891 cell lines in vitro, and investigated the association between cytotoxic activity and adenoviral receptor expression. In this study, we evaluated the most appropriate way to administer telomelysin (OBP-301) in the treatment of squamous cell carcinoma of the head and neck (SCCHN), and assessed the effect of OBP-301 in large subcutaneous KCCT873 human SCCHN tumors in immunodeficient mice. We also compared antitumor responses following three intratumoral (i.t.) injections of OBP-301 given daily, every 2 days or weekly. To investigate the mechanism of the antitumor effect, we evaluated cellular infiltration in treated tumors. OBP-301 showed remarkable antitumor activity against large KCCT873 tumors, and three treatment schedules produced similar antitumor effects. The weekly regimen also significantly reduced the growth of large tumors. Immunochemistry revealed that macrophages, but not natural killer cells, were responsible for tumor regression. A regimen of three weekly injections of OBP-301 has remarkable antitumor effects against large KCCT873 tumors. These results may provide a new platform for treating patients with localized SCCHN. IntroductionSquamous cell carcinoma of the head and neck (SCCHN) accounts for 5% of newly diagnosed cancers in adults in the US and 8% of cancers worldwide (1). Most patients are treated with various combinations of surgery, radiotherapy and systemic agents, but treatment fails in about half of patients (2). In light of the poor outlook for patients with recurrent disease, additional effective local-regional therapies are clearly required for the treatment of SCCHN. Conditionally replicating viruses targeted to tumors are being developed as a novel class of oncolytic agents. Oncolytic virotherapy has been evaluated in clinical trials of patients with SCCHN. For example, in a phase II trial, the addition of systemic cisplatin or 5-fluorouracil following direct intratumoral (i. t.) injection of the oncolytic adenovirus ONXY-015 resulted in clinical regression of SCCHN tumors (3).Telomerase is a ribonucleoprotein complex responsible for the complete replication of chromosomal ends (4). It is expressed in >85% of human cancers (5) but in only a few normal somatic cells (6). Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated to expression of human telomerase reverse transcriptase (hTERT) (7). hTERT can therefore be exploited as a cancer-specific promoter.Telomelysin (OBP-301) is a telomerase-specific replicationcompetent adenovirus vector in which the hTERT promoter element drives the expression of E1A and E1B genes, which are linked to an internal ribosome entry site (8,9). Telomelysin has been shown to selectively kill human cancer cells (8-11). In infected human tumor cells in vitro, OBP-301 replication produces the endogeno...

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Section: Introductionmentioning

confidence: 99%

Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

et al. 2009

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“…Such signals make DCs capable of priming Ag-specific T cells (9,10,14). Viruses are recognized by the innate immune system through various host pattern-recognition receptors (12,15) to stimulate the immune system and induce CTL activity (16), even in a context of strong immunosuppression. Oncolytic viruses as new cancer therapeutics are non-pathogenic, naturally occurring RNA or DNA viruses.…”

Section: Introductionmentioning

confidence: 99%

Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity

Fournier

Arnold²,

Wilden³

et al. 2011

Int J Oncol

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Abstract. Newcastle disease virus (NDV) is a negative sense RNA paramyxovirus of birds which in human tumor cells, in contrast to human non-tumor cells, has shown replication competence leading to tumor cell death (i.e., tumor selectivity and viral oncolysis). Our study demonstrates that this virus induces high levels of pro-inflammatory cytokines in the bronchial lavage fluid of mice after nasal application and also in vitro in human dendritic cells (DCs). NDV is known as a very efficient inductor of type I interferon (IFN). The presented data show the key role played by the cell surface receptor to type I IFN (IFNAR) but not by the interferon transcription factors IRF-3 and IRF-7 in the induction of the important pro-inflammatory cytokine IL-12 upon transcription of NDV genes in DCs. We show that NDV activates in infected cells the helicase RIG-I. In Tregs, the activation of RIG-I was shown in other studies to inhibit the suppressive function of these cells. We thus conclude that NDV in tumor therapy may help to stimulate T effector cells but also to block Treg cells, thereby alleviating a brake to antitumor activity.

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“…OBP-301 can replicate in and lyse only cancer cells but not normal cells, and its strong cytotoxic activity were shown in a variety human cancer cells (15 -17). Also, OBP-301-mediated oncolysis induces uric acid production as a danger signal and stimulates CTL activity via proteasome activator upregulation (18).…”

Section: Introductionmentioning

confidence: 99%