Current Cancer Therapy Reviews - Volume 11, Issue 3, 2015

Oncolytic adenoviruses (Ad) that selectively replicate in cancer cells are emerging as a promising new modality for cancer treatment. The most attractive feature of oncolytic Ad is its ability to destroy cancer cells through a distinctive and unique function in which the virus selectively replicates and destroys tumors by cell lysis, a function that no anti-cancer drugs can mimic. Moreover, coupling the lytic function of oncolytic Ad with virus- mediated expression of therapeutic gene, termed “armed oncolytic Ad”, has been exceedingly promising in preclinical settings. However, systemic delivery of oncolytic Ad inevitably induces antiviral immune responses and nonspecific uptake to the liver due to Ad’s native tropism, resulting in short blood retention time, low therapeutic efficacy, and hepatotoxicity. Therefore, alternative strategies are required to enhance delivery of oncolytic Ad to targeted tumor tissues. To this end, surface modification of Ad by chemical and genetic engineering has been extensively studied. Surface modification can be categorized into two major subsets which are physical modification and chemical modification, resulting in alteration of Ad’s native tropism and enhancement of therapeutic efficacy and safety on systemic delivery of oncolytic Ad. These attributes make hybrid delivery system, which combines viral and non-viral carrier, a promising strategy for cancer gene therapy as each carrier’s strengths contribute to synergistic enhancement in delivery and therapeutic efficacy. Here, we describe various strategies currently being applied to maximize the therapeutic efficacy of oncolytic Ad. We also discuss advances in the integration of viral and non-viral nanomaterials aimed to overcome the limited clinical application of conventional Ads which will enable effective treatment of disseminated tumors via systemic injection.

An ultimate goal of the developers of cancer genetherapy/virotherapy is to develop a device enabling systemic treatment of the patients with advanced or spread diseases. The targeting at the level of infection, which can define the initial distribution following intravenous administration, is considered to be the most important for realization of systemic therapy. Adenovirus which has very high in vivo transduction efficiency is an attractive vector for designing novel cancer therapeutics for systemic therapy, and we and others have been working on this issue in the field of oncolytic adenovirus (OAd). However, the success rate of incorporation of targeting ligand to OAd without losing potency has been extremely low. We thus decided to run a screening of the ligand sequence in the adenoviral capsid format, and chose to replace 7 amino acids sequence mediating the initial binding of the virus to the receptor of adenovirus. By modifications and optimization of the production procedure, we achieved >1010 diversity, which permits the full coverage of 7 random amino acid library. Our high-throughput screening system is powerful enough to enable the screen of the adenovirusformat high-diversity library, and identified the specific targeting ligand in a highly efficient manner. In in vivo models, Infectivity Selective OAd (ISOAd) showed strong and selective anti-tumor effect in the xenotrafts of MSLN-positive pancreatic cancer cell line. The intravenously injected ISOAd targeting mesothelin showed a surprisingly strong antitumor effect, which was equivalent or stronger than that of intratumoral injection. These data indicate the possibility of systemic clinical application with ISOAd. While OAd is a very promising direction, the application of this novel series of vectors is not limited to OAd. Our screening strategy also produces many targeting ligands for therapeutic vector development. Our novel ligand identification system has broad implications to various purposes, and further development is anticipated.

Oncolytic virus therapy has recently been recognized as a promising new treatment option for cancer. The strategy is to use genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells, without harming normal cells. Herpes simplex virus type 1 (HSV-1) has been well studied and has many advantages for the use in cancer therapy, making it the mainstay of current clinical trials of oncolytic virus therapy. Numerous preclinical and clinical studies of oncolytic HSV-1 have demonstrated its safety and antitumor efficacy, the latter of which is mainly attributable to its direct cytocidal effect. However, recent studies have also suggested that oncolytic HSV-1 elicits host antitumor immunity and induces immunogenic cancer cell death, thus offering possibilities for multifaceted strategies by focusing on enhancement of host anticancer immunity. In this review, we summarize the history and current status of preclinical and clinical studies of oncolytic virus therapy using HSV-1.

A multidisciplinary approach of combining surgery, chemotherapy and radiotherapy has remained the accepted standard management for various types of human cancer. However, many new treatment options have recently become available, including molecular targeted therapies, immunotherapies and oncolytic virotherapies. Replication-selective tumor- specific viruses have been designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. We constructed an attenuated adenovirus 5 vector, telomelysin (OBP-301), in which the telomerase-specific promoter drives expression of viral replication-inducible E1 genes. Although telomelysin alone exhibited substantial antitumor effects both in animal models and in clinical trials, telomelysin has the potential to be the first-in-class oncolytic virus for combination therapy based on our current understanding of the molecular mechanisms. Telomelysin sensitizes human cancer cells to ionizing radiation by inhibiting the radiation-induced DNA repair machinery, and also eliminates radio-resistant quiescent cancer stem-like cells by promoting cell cycle entry. A clinical trial of intratumoral administration of telomelysin with radiotherapy in esophageal cancer patients is currently underway. This article reviews recent highlights in the rapidly evolving field of multidisciplinary therapy with telomelysin.

Recently, substantial attention has been focused on cancer treatments using oncolytic viruses, which may result in a paradigm shift in conventional cancer therapy through the use of these viruses either alone or in combination with other therapeutics. Thus far, the cancer-killing mechanism of oncolytic viruses has been dependent on selective viral replication in cancer cells. However, UV-irradiated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) with membrane fusion activity selectively induce apoptosis in human cancer cells but not non-cancerous cells, although neither viral genome replication nor viral protein synthesis occurs in infected cells. The mechanism of HVJ-E-induced cancer cell killing involves the introduction of viral genome RNA fragments into the cytoplasm via membrane fusion and the subsequent activation of a retinoic acid-inducible gene-I (RIG-I)-like receptor signal, which results in the upregulation of apoptotic genes such as tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and Noxa through the phosphorylation of interferon-regulatory factor (IRF)-3 and -7. In neuroblastoma cells lacking caspase 8, HVJ-E induces programmed necrosis (necroptosis) through the activation of cytoplasmic calcium, which in turn activates calcium-calmodulin-depedent protein kinase to phosphorylate receptorinteracting protein (RIP)-1 and -3. In addition to directly killing cancer, HVJ-E elicits anti-tumor immunity by recruiting immune cells to the tumor microenvironment, facilitating the maturation of dendritic cells, enhancing natural killer (NK) cell activity and ultimately activating killer T cells targeting cancers. Anti-tumor immunity is also achieved via the RIG-I-like receptor signal triggered by cytoplasmic viral RNA fragments, independent of toll-like receptor signaling. Moreover, the fusion protein of HVJ-E acts directly on dendritic cells and macrophages to produce interleukin (IL)-6, which attenuates the function of regulatory T cells. Thus, HVJ-E provides a multi-modal strategy for cancer therapy.