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

Abstract

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...

Sulfide Capacities of Solid Oxides in Calcium-Aluminate Systems

“…This result shows the decomposition of C 3 A to the high sulfur phase and low Al phase. As described in the previous section, C 3 A is decomposed into CaS and C 12 A 7 ; thus, the present results validate this phenomenon.…”

“…The CaO-Al 2 O 3 system inclusion is usually formed by the addition of Ca to Al-killed steel, for modifying Al 2 O 3 to a less harmful oxide with a low melting point. However, CaS precipitation is observed on this inclusion [1][2][3][4] and causes pitting corrosion in ferritic stainless steel. 5,6) Several studies have been conducted for determining the mechanism of CaS precipitation on the CaO-Al 2 O 3 system inclusions.…”

Development and application of oncolytic viruses as the nemesis of tumor cells

“…Back in 2005, China approved the first OV, an Ad called H101 ( Liang, 2012 ; Wei et al, 2018 ), for the treatment of squamous cell carcinoma of the head and neck (SCCNH; Garber, 2006 ). Ads are used to treat several types of cancer, including melanoma ( García et al, 2019 ; Milenova et al, 2021 ), lung cancer ( Watanabe et al, 2006 ), colorectal cancer ( Kuhn et al, 2008 ), prostate adenocarcinoma (PRAD ; Chen et al, 2001 ; DeWeese et al, 2001 ; Ramesh et al, 2006 ; Small et al, 2006 ; Huang et al, 2008 ; Burke et al, 2012 ; Rojas-Martínez et al, 2013 ; Packiam et al, 2018 ; Oronsky et al, 2022 ), malignant glioma (MG; Chiocca et al, 2004 ; Lang et al, 2018 ; Kieran et al, 2019 ; Carpenter et al, 2021 ), ovarian cancer (OC; Kimball et al, 2010 ; Kim et al, 2013 ; Vassilev et al, 2015 ), head and neck cancer (HNC; Chang et al, 2009 ; Nakajima et al, 2009 ), and solid tumors ( Lin et al, 2007 ; Li et al, 2009 ; Nemunaitis et al, 2010 ; Nokisalmi et al, 2010 ; Pesonen et al, 2012 ; Machiels et al, 2019 ).…”