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ILAR J. 2016 March 31; 57(1): 73–85.
Published online 2016 March 31. doi:  10.1093/ilar/ilv048
PMCID: PMC4816122

Murine Tumor Models for Oncolytic Rhabdo-Virotherapy

Abstract

The preclinical optimization and validation of novel treatments for cancer therapy requires the use of laboratory animals. Although in vitro experiments using tumor cell lines and ex vivo treatment of patient tumor samples provide a remarkable first-line tool for the initial study of tumoricidal potential, tumor-bearing animals remain the primary option to study delivery, efficacy, and safety of therapies in the context of a complete tumor microenvironment and functional immune system. In this review, we will describe the use of murine tumor models for oncolytic virotherapy using vesicular stomatitis virus. We will discuss studies using immunocompetent and immunodeficient models with respect to toxicity and therapeutic treatments, as well as the various techniques and tools available to study cancer therapy with Rhabdoviruses.

Keywords: biotherapeutic, cancer, efficacy, murine model, oncolytic virus, treatment, tumor, vesicular stomatitis virus (VSV)

Background

The lack of options available for patients with chemotherapy-resistant, advanced, aggressive, or systemic disease is pushing the field of cancer therapy to progress rapidly, with novel strategies being developed. Of the many promising approaches that recently emerged, oncolytic viruses (OVs) have the potential of treating disseminated diseases, targeting various tumor types, and inducing durable systemic antitumor immune responses with minimal side effects compared with current therapies (Singh et al. 2012). OVs are selected or designed to specifically destroy cancer cells (Zeyaullah et al. 2012). Although there are many different OVs currently being investigated around the world, the focus of this review is on the Rhabdovirus family member vesicular stomatitis virus (VSV). VSV is a single-stranded, negative-sense RNA virus that can infect both insects and mammals (Kuzmin et al. 2009). These viruses are highly sensitive to the antiviral activity of interferon (IFN), and thus in normal cells, infection is controlled through the induction of the IFN response (Stojdl, Lichty, et al. 2000). However, several tumor cell lines (SK-MEL3, LNCAP, LC80, and OVCA 420), unlike normal cells (human ovarian surface epithelial cells, primary normal human prostate epithelium, and OSF7 cells), have defects in the IFN pathway, which allows Rhabdoviruses to selectively infect and subsequently kill these malignant cells (Hanahan 2000; Stojdl, Lichty, et al. 2000). Various recent reviews focus on the biology, neurotropism, genetic engineering, oncoselectivity, and safety of VSV and thus will not be discussed here (Hastie and Grdzelishvili 2012; Hastie, Cataldi, et al. 2013; Lichty et al. 2004).

Various animal models can be used to study OVs. Classically, safety studies for preclinical data are performed in nonhuman primates because they are genetically closer to humans, but for ethical reasons, tumors cannot be implanted in these animals, and this severely limits the use of this model for efficacy studies (Jenks et al. 2010; Johnson et al. 2007). Companion animals such as canines and felines can also accurately reflect some aspects of human disease because of the natural occurrence of cancer in these animals. However, the limited number of test subjects with similar tumor types constitutes one of the main limitations of this model. Alternatively, purpose-bred canine models have been used in dose-escalation studies, but again, the typically small number of subjects is considered a major limitation (LeBlanc et al. 2013). Importantly, it was reported that canines might be resistant to the neurotoxicity of OVs, which emphasizes the potential differences between species and the necessity of assessing the response to treatment in various models before testing in humans. Smaller animal models like rats and mice confer the undeniable ease of including more animals per experiment in genetically identical backgrounds. The availability of multiple chemical carcinogens and genetically modified mice that predicatively develop specific cancers, as well as tumor cell lines that can be implanted in vivo, provides a powerful set of tools for large-scale, well-controlled studies. Rat tumor models have been used to demonstrate safety and efficacy of OV treatments (Jenks et al. 2010; Kurisetty et al. 2014) but will not be addressed here. Also, promising alternatives for the in vivo study of human samples are chicken embryos (Jayachandran et al. 2015) and zebrafish (Chiavacci et al. 2014; Feitsma and Cuppen 2008), although, to our knowledge, these models have not been reported to be used for OV studies. Although each model has pros and cons, factors such as cost, housing, availability, biology, and ethics should be considered in the selection of the appropriate model that will best answer the specific questions of each study.

Mouse Tumor Models for VSV Studies

Various reviews summarize available mouse models for cancer therapeutics studies (Frese and Tuveson 2007; Olive and Tuveson 2006; Sharpless and Depinho 2006). These reviews describe in great detail the advantages and disadvantages of syngeneic immunocompetent, immunodeficient, and xenograft murine models. A wide variety of tumors can be implanted or induced in these animals in different organs. Many tumor cell lines can be injected subcutaneously to form a primary tumor, intravenously to colonize the lungs, or orthotopically to recapitulate the appropriate tumor microenvironment. In this section, we will discuss some of the more commonly used models in the study of VSV. Details are summarized in Table 1.

Table 1
Murine tumor models for vesicular stomatitis virus (VSV) efficacy studies

Subcutaneous tumor models provide the advantage of easy access to the tumor for treatment and direct monitoring. They are the most common models used to study OVs, with breast (4T1, TS/A, D1-DMBA3, D2F2, EMT6), colon (CT26, MC38), melanoma (B16), and renal (Renca) cancer cell lines having been previously described (Ahmed et al. 2010; Arulanandam, Batenchuk, Varette, et al. 2015; DeRose et al. 2011; Ebert et al. 2005; Edge et al. 2008; Fernandez et al. 2002; Garijo et al. 2014; Janelle et al. 2014; Jha et al. 2013; Kim et al. 2012; Kottke et al. 2008; Le Boeuf et al. 2010; Lemay et al. 2012; McCart et al. 2001; Moussavi et al. 2010; Nanni et al. 1983; Obuchi et al. 2003; Rintoul et al. 2012; Rommelfanger et al. 2012; Stephenson et al. 2012; Stojdl et al. 2003; Wongthida, Diaz, Galivo, et al. 2011). However, to recapitulate closely what occurs in the course of human disease, more clinically relevant sites of implantation are required.

Intravenous administration of tumor cells allows for colonization of the lungs and can also mimic systemic disease. Various cell lines can be injected intravenously as artificial models of lung metastasis. Of these, 4T1, B16, CT26, and TS/A have been used for oncolytic Rhabdovirus studies (Ebert et al. 2005; Fernandez et al. 2002; Lemay et al. 2012; Obuchi et al. 2003; Rintoul et al. 2012; Stephenson et al. 2012; Stojdl et al. 2003; Zhang et al. 2014). Also, hematologic cancer models such as leukemia/lymphoma and multiple myeloma are studied by intravenous administration. Of these, L1210, EL4, and 5TGM1 were used to assess efficacy of VSV virotherapy (Conrad et al. 2013; Goel et al. 2007). Finally, lung cancer cell lines (e.g., Lewis lung carcinoma) are established by intravenous injection as well (Hirasawa et al. 2003; Qiao et al. 2008). Intracardial tumor cell administration is another route that also mimics disseminated disease. Because most tumor cells lodge in the lungs after intravenous administration (Warren and Gates 1963), intracardiac injection allows the initial bypass of the lungs and permits tumor cells to circulate to other organs. Indeed, injection in the left ventricle of the heart can be used to establish tumors in the bones or brain (Campbell et al. 2012). This method allows one to recapitulate late-stage metastatic disease.

An alternative for the generation of systemic disease is the orthotopic engraftment of tumors using syngeneic or xenogeneic models. Indeed, it has been shown that orthotopic xenografts metastasize much more readily than subcutaneous xenografts and are thus better representative of human cancers (Hoffman 2015). This also allows the study of various aspects of cancer biology that may impact OV therapy, such as poor tumor perfusion/hypoxia, tumor-associated stromal elements, and immune cell infiltration (Clark and Vignjevic 2015; Vanharanta and Massagué 2013). To this end, tumors can be implanted directly in the brain, the pancreas, or the mammary fat pad. The injection of cells into the mammary fat pad is easy to perform in breast cancer models such as 4T1, E0771, and EMT6 and allows for a recapitulation of the metastatic route (lungs, liver, and bones) observed in human breast cancer patients (Pulaski and Ostrand-Rosenberg 2001). For other orthotopic sites such as the kidney (Renca), the pancreas (Panc02), the brain (U87, CT2A, CT26 and B16F10), the spleen, and the liver, injections can be more challenging. However, we found that the use of Hamilton syringes and needles specifically tailored for precise injections facilitates the successful delivery of cells (Devaud et al. 2013; Kato et al. 2014; Shevchenko et al. 2013; Tracz et al. 2014; Vonlaufen et al. 2008).

Transgenic models of cancer have the advantages of having predictable timing and known genetics, are syngeneic, and show similar histology and biology to human disease. Ovarian (MISIISTAg, Wv) (Arulanandam, Batenchuk, Varette, et al. 2015; Capo-chichi et al. 2010), prostate (PTEN−/−, TRAMP) (Moussavi et al. 2010; 2013), and pancreatic (KC) (Hastie, Besmer, et al. 2013) transgenic cancer models were previously used for VSV efficacy studies. Importantly, these models allow the study of common mutations in specific cancer types and how these may impact OV therapy (Balachandran et al. 2001).

Finally, chemical induction of tumors recapitulates human disease that results from exposure to mutagenic or inflammatory agents, as is the case with melanoma (UV light), lung carcinoma (tobacco), and hepatocellular carcinomas (chronic alcohol consumption and hepatitis C virus infections). Indeed, these diseases are highly heterogeneous and carry a high mutational load (Alexandrov et al. 2013). A wide variety of carcinogens are available for murine skin, lung, and liver cancer models (Nassar et al. 2015; Simanainen et al. 2015; Westcott et al. 2014). One of the main limitations of this approach is the lengthy period of time required to develop tumors. A thioacetamide-induced hepatocellular carcinoma model was previously used to study VSV in rats (Altomonte et al. 2013), but we could not find any report of chemically induced cancer models used for OV studies in mice.

Mouse Models to Study Immune Responses

OVs are more and more appreciated for their ability to induce tumor-specific immune responses, a property that is crucial for efficient control of tumors (Lichty et al. 2014). The use of athymic nude mice that lack T cells or SCID (severe combined immunodeficiency) mice that lack B cells and T cells and antibody-mediated depletion of specific immune cell populations are convenient tools to discriminate the immune compartments involved in the generation of antitumor immunity and OV efficacy (Bergman et al. 2007; Willmon et al. 2011; Wongthida, Diaz, Pulido, et al. 2011; Wongthida et al. 2010).

Human Samples and Cell Lines

The in vivo study of human tumors is challenging. Although primary patient samples provide the obvious advantage of being relevant to human disease, their access and numbers are limited. These samples can be used for ex vivo analysis and allow for a wide range of conditions to be tested. We previously published a detailed visual protocol describing the ex vivo study of VSV using tumor cores (Diallo et al. 2011). Unfortunately, the ex vivo study of biopsies does not reflect the conditions present in vivo. In addition, the engraftment of human tumor cell lines into mice presents the challenge of xeno-rejection and thus requires the use of immunocompromised animals. One important factor to consider using immunodeficient mice for OV studies is their increased susceptibility to viral infection. Indeed, the lethal dose of virus was shown to be drastically reduced for immunocompromised animals (Huneycutt et al. 1993; Thomsen et al. 1997). Most human cell lines are grown in nude or SCID mice (Carreno et al. 2009; Choi et al. 2014; Simeoni et al. 2013). These animals have been used for VSV studies using human melanoma (SK-MEL-3), plasmacytoma (KAS 6/1), glioblastoma (U87), colon (SW620, A549, HT29), prostate (DU145, PC3), pancreatic (Miapaca-2, Panc 03.27), ovarian (ES-2, OVCAR8), kidney (ACHN, 786-O), cervical (HeLa), and tongue (SCC25) cancers (Ayala-Breton et al. 2013; Blackham et al. 2014; Breitbach et al. 2007; Edge et al. 2008; Ilkow et al. 2015; Jha et al. 2013; Le Boeuf et al. 2010; 2012; Muik et al. 2014; Stojdl et al. 2003; Stojdl, Lichty, et al. 2000; Zhao et al. 2014).

Other immunodeficient animals, such as NOD (nonobese diabetic) SCID mice are used for tumor models that are more easily rejected, as well as for patient-derived samples (Kim et al. 2009). These mice are highly immunocompromised; they lack T, B, and functional NK cells and thus require special housing and handling under specific pathogen-free conditions. They are more expensive and difficult to work with regarding surgery/anesthesia, and complications such as infections by environmental pathogens can arise (Kim et al. 2009). To increase the chances of successful engraftment of patient samples into NOD SCID mice, matrigel or cultrex can be coinjected (Benton et al. 2011). These products are a mix of growth factors that stimulate tumor growth and basement membrane matrix proteins that structurally form a scaffold to support tumor formation. By providing these key components of the natural tumor microenvironment, these mixtures were shown not only to favor xenograft development but also to increase tumor growth rate and metastatic potential (Fridman et al. 2012). Pancreatic and breast cancer patient samples have been successfully engrafted and passaged for VSV studies using these matrixes (DeRose et al. 2011; Ilkow et al. 2015) (Figure 1).

Figure 1
In vivo vesicular stomatitis virus (VSV) infection of human breast cancer xenografts. Human triple-negative breast cancer samples were implanted into mammary fat pad–cleared NOD SCID mice as previously described (DeRose et al. 2011). When tumors ...

Routes of Virus Delivery

Many options exist for delivering virus in vivo, with the common routes being intravenous, intratumoral, intranasal, intraperitoneal, and subcutaneous. In efficacy studies, intravenous and intratumoral injections are the most common and clinically applicable methods, whereas intravenous, intranasal, and intracranial injections are most often used for toxicity studies (Stojdl et al. 2003). The intraperitoneal route, which is well suited to treat diseases such as mesothelioma and peritoneal carcinomatosis, and subcutaneous route of delivery are less commonly used and thus will not be discussed here. The injection methods and the models in which they were used are summarized in Table 1.

Direct intratumoral injections are used to administer the virus to subcutaneous and to surgically implanted tumors, such as those in the brain or liver. Immediate local delivery is achieved, with the full dose of virus being delivered to the site of interest. The level of difficulty is low, but precautions must be taken to avoid leakage and subsequent loss of viral dose as a consequence of high interstitial fluid pressure within the tumor (Jain 1990). This route is used to administer OVs in some clinical trials and thus remains relevant to the treatment of human disease (Heo et al. 2013). Although intratumoral injections are easy, they limit delivery of the treatment to the primary site of injection and can be difficult to perform in some anatomical locations such as kidneys, lungs, brain, or ovaries without surgical intervention or the aid of sophisticated equipment (i.e., ultrasound, stereotactic unit).

In mice, systemic delivery of virus by intravenous injection is often performed by the lateral tail vein. Intravenous injection allows for the delivery of virus to primary tumors and also to metastases (Breitbach et al. 2007; Fisher 2006). Unfortunately, drawbacks include limitations in the maximum volume delivered (approximately 100 μl) and the challenge of administering multiple doses, especially when the animals are dehydrated as a result of the disease or side effects of the treatment. Other factors to consider with intravenous delivery are the low efficiency of delivery to the tumor and the increased risk of toxicity to normal tissues because the virus is delivered systemically. Although a single bolus of virus injected intravenously is the simplest approach, gradual delivery, which mimics a clinical scenario, can be performed using various kinds of pumps. Programmable pumps are affordable and allow for slow infusion through the tail vein through a catheter. This technique was previously used to administer various substances to mice and other animals (Matsuo et al. 1998; Nilaver et al. 1995). Another type of device known as an osmotic pump requires surgical implantation and has mostly been used to deliver drugs over a specified time course and rate (Mirandola et al. 2011; Shibata et al. 2008).

Intranasal injections are easy to perform through direct administration into the nares of the animal. Mice must be anesthetized to minimize chances of sneezing, which could result in loss of virus during the procedure (Wollmann et al. 2010). When administered intranasally, the virus will typically infect the brain, olfactory system, and respiratory system (Ozduman et al. 2008). This route has been previously used to study VSV-associated neurovirulence (Edge et al. 2008; Stojdl, Abraham, et al. 2000; Wollmann et al. 2015).

Studying the Virus–Tumor Interaction

Studying how OVs interact with the host and the tumor can provide valuable insight on their mechanism of action and also reveal important information on how to improve their safety and effectiveness. The ability to monitor virus replication, both quantitatively and qualitatively, is invaluable in this regard. Various techniques are available to analyze the presence of virus in tumors and normal tissues. Virus titration, quantitative polymerase chain reaction (qPCR), bioluminescence/fluorescence imaging, and immunohistochemistry (IHC) are commonly used methods. Whereas titration by plaque assay measures infectious virus particles (plaque forming units [PFUs]), qPCR quantifies genome copies and thus is not a measure of infectivity. Both techniques have been used in several studies using VSV (Breitbach et al. 2007; Eisenstein et al. 2013). On the other hand, bioluminescence and fluorescence imaging requires the use of virus variants that express fluorescent proteins or luciferase. Instead of directly quantifying the virus, this technique visualizes and measures the expression of a reporter transgene and can be performed on anesthetized animals, which confers the advantage of allowing for multiple readings without having to kill the animals, and is therefore ideally suited for kinetic analyses of virus replication. Bioluminescence imaging using the In Vivo Imaging System has been used in various VSV studies (Arulanandam, Batenchuk, Varette, et al. 2015). Figure 2 shows an example of bioluminescence imaging of a VSV-expressing luciferase in various tumor models and anatomical locations. A similar approach is to use a virus variant encoding a sodium iodide symporter gene (NIS). Using this technique, the animals must be injected with radioactive iodine before imaging using a small animal PET/CT scan (Ayala-Breton et al. 2013; Goel et al. 2007; LeBlanc et al. 2013). Another way to visualize VSV is by IHC. This method requires the use of an antibody against the virus and takes more time to perform compared with other methods described but provides the advantage of characterizing the localization of the virus within the tumor or tissue of interest. Virus localization can also be correlated with other markers of interest, such as markers of apoptosis (Breitbach et al. 2007). IHC for VSV was performed in various murine and human tumor models. An example of IHC performed in a xenograft model of human breast cancer treated with VSV is provided in Figure 1. Finally, the window chamber is an apparatus that can be surgically placed on a mouse for the visualization of the formation of tumors and their associated blood vessels in real time. Both dorsal and mammary window chambers have been used and allow for intravital microscopy using fluorescence imaging (Palmer et al. 2012). The window chamber has been used to study various established human and murine tumor cell lines, such as breast (MDA-MB-231 and 4T1) (Jin et al. 2014; Rajaram et al. 2013) and renal (Caki-2) carcinoma models, for visualization of the tumor microvasculature (Biel et al. 2014). Visualization of a fluorescent version of vaccinia, another OV, within the tumor vasculature was previously performed using the window chamber model (Arulanandam, Batenchuk, Angarita, et al. 2015), but to our knowledge, there are no published reports using this technique to study VSV.

Figure 2
Bioluminescence imaging of vesicular stomatitis virus (VSV) in various murine tumor models. Mice bearing various tumor types in different locations were analyzed by bioluminescence imaging 24 hours after treatment with VSVΔ51-luciferase administered ...

One of the main advantages of using animal models over in vitro studies is the presence of a complete tumor microenvironment. The different constituents of the tumor microenvironment, which include tumor blood vessels, cancer-associated fibroblasts, tumor-infiltrating immune cells, and extracellular matrix proteins, all interact with OVs and can dramatically influence the delivery and efficacy of OV therapeutics. For example, it has been shown that intravenous delivery of VSV results in the infection of tumor vasculature, which results in vascular shutdown, a phenomenon that slows down tumor growth (Breitbach, De Silva, et al. 2011). This has also been seen in patients after OV therapy (Breitbach, Burke, et al. 2011). The mechanism of selective infection of tumor endothelium, but not normal endothelium, involves the secretion of vascular endothelium growth factor (VEGF) by the tumor endothelium, which subsequently induces the expression of PRD1-BF1/Blimp1 to increase viral replication in blood vessels (Arulanandam, Batenchuk, Angarita, et al. 2015). Cancer-associated fibroblasts, another cellular component of the tumor microenvironment, were recently demonstrated to sensitize tumors to OV infection through the secretion fibroblast growth factor 2 (FGF2) (Ilkow et al. 2015). Tumors are often infiltrated by several immune cell types, and these can influence virus replication as well as modulate antitumor activity. For example, one study demonstrated that inhibition of chemokine secretion by an engineered VSV resulted in a decrease in the recruitment of neutrophils and NK cells to the tumor after virus infection, and this led to a dramatic increase in virus replication and efficacy (Wu et al. 2008).

Noncellular components of the tumor microenvironment can also impact OV therapy. It has been demonstrated that interstitial collagen restricts the spread of herpes virus within the tumor, and therefore exogenous expression of collagenase was shown to increase virus spreading within the tumor, which improved efficacy (McKee et al. 2006). Subsequent strategies to successfully improve OV cell-to-cell spread or diffusion within tumors, all of which target various extracellular matrix components for degradation, include coadministration with trypsin (various targets) or hyaluronidase (hyaluronan) and encoding matrix metalloproteinases or relaxin (both degrade collagen) within the virus (Cheng et al. 2007; Ganesh et al. 2008; Kim et al. 2006; Kuriyama et al. 2000).

Studying the Virus–Host Interaction

The circulatory system is a hostile environment for VSV. Circulating antibodies, complement nonspecific binding to circulating cells and serum components, as well as uptake by specialized liver macrophages known as Kupffer cells, all of which contribute to minimizing the effective dose of virus delivered to tumors (Evgin et al. 2015; Ferguson et al. 2012). Given the challenges of systemic delivery of OVs in the face of a host immune system that is highly evolved to recognize and eliminate viruses, our group and others have explored different strategies to overcome these barriers. It has been demonstrated that the depletion of Kupffer cells using clodronate liposomes successfully increased systemic delivery of oncolytic adenovirus to tumors (Shashkova et al. 2008). Another approach is to use cells as delivery vehicles, or Trojan horses, for OVs (Bell and Roy 2013; Willmon, Harrington, et al. 2009). Internalization of the virus by the cell carrier not only protects the virus from immune recognition and neutralization, but the virus can also replicate within the cell carrier, thus increasing the OV dose delivered to tumors. Several cell types have been explored as carriers for the delivery of OVs, including tumor cells, T cells, dendritic cells, insect cells, and myeloid-derived suppressor cells (Eisenstein et al. 2013; Ilett et al. 2011; Kottke et al. 2008; Power et al. 2007; Roy et al. 2015). Importantly, we have shown that cell carriers can deliver VSV to tumors in the presence of high levels of VSV-neutralizing antibodies, whereas naked virus was efficiently neutralized (Power et al. 2007). Such strategies allow for multiple doses of virus to successfully be delivered to the tumor, therefore increasing the therapeutic effects.

One of the main concerns regarding systemic administration of virus is the risk of toxicity associated with infection of normal tissues. This risk is even greater using more potent viruses with increased cytotoxic activity. Although virus replication in nontumor cell lines can be tested in vitro, the most relevant way to assess tumor specificity is by determining the biodistribution of the virus after treatment. Typically, organs are harvested after treatment, and the virus is quantified using the techniques described previously. To minimize toxicity to normal cells and increase safety, attenuated versions of VSV have been developed. VSVΔ51, AV1, and AV2 (Stojdl et al. 2003), as well as a VSV variant expressing IFNβ (Willmon, Saloura, et al. 2009), are a few examples. An alternative approach for improving the safety profile of OVs is through microRNA detargeting. By encoding the target sequence of microRNAs that are expressed in normal tissues, but not in tumor tissues, within the viral genome, tumor selectivity can be improved (Edge et al. 2008; Kelly et al. 2008).

Knockout mice can also provide valuable information into the mechanisms of virus clearance by the host. A good example is the PKR-/- mouse, which lacks a gene involved in the induction of the IFN antiviral response (Abraham 1999). These mice are hypersensitive to VSV infection, with a dose of less than 10 PFUs resulting in neurotoxocity, whereas attenuated mutants were tolerated at doses higher than 1 × 107 PFUs (Stojdl et al. 2003). The IFN α and β receptor null mice have also been used for toxicity studies because they are more susceptible to viral infections. Previous results showed that, whereas wild-type mice were unaffected by 50 PFUs of VSV, the knockout mice succumbed to infection within 3 to 6 days (Muller et al. 1994). Similar results were obtained using another mouse strain that is defective in the IFNα/β pathway: the STAT1 knockout (Meraz et al. 1996).

One mechanism by which OVs eliminate tumors is by their capacity to stimulate the immune system. It is now accepted that OVs like VSV induce antitumor immunity, therefore providing a long-lasting systemic protection (Mahoney and Stojdl 2013). In an attempt to improve this aspect of OV therapy, various viruses have been engineered to encode immune-stimulatory molecules. These were recently reviewed elsewhere and will not be listed here (Lichty et al. 2014). Standard immunology techniques such as flow cytometry and ex vivo restimulation with specific antigens can be used to study the antivirus and antitumor immune responses. Interestingly, for some antigens, the specific T cell epitopes are known, which allows for ex vivo restimulation with peptides instead of whole cells or purified molecules. For example, the B16 melanoma cell line expresses the well-characterized dopachrome tautomerase molecule (DCT), for which the exact sequence presented at the cell surface is known. Tumor cell lines can also be engineered to stably express foreign antigens such as ovalbumin (OVA) for which the epitopes presented at the cell surface are known (Rötzschke et al. 1991), thereby facilitating the study of OV-induced immune responses. Similarly, research tools, such as the OTI and OTII mice, which have peripheral T cells that are specific for ovalbumin, are available. The B16-OVA tumor model and OTI mice were previously used to study antitumor immunity after VSV treatment (Kottke et al. 2008).

Studying the Virus–Host–Tumor Interaction

The methods used to assess efficacy after OV treatment are the same as for other cancer therapies. Tumor growth is assessed by calculating the tumor volume using caliper measurements of length and width of the tumors (Edge et al. 2008; Fernandez et al. 2002). For lung tumors, the quantity and size of lung metastasis can be assessed by weighing the lungs, perfusing them with India ink, or directly visualizing them (Ahmed et al. 2010; Shi et al. 2009; Shibata et al. 2008; Stojdl et al. 2003). Of course, overall survival can also be assessed with Kaplan-Meier survival curves (Qiao et al. 2006; Stojdl et al. 2003). Several studies using these methods are reported in Table 1.

Combination Strategies

With the objective of improving the efficacy of OV therapy, several groups have combined viruses with other cancer therapies (Ottolino-Perry et al. 2010). The combination of radiotherapy with VSV was shown to be one of many successful approaches (Alajez et al. 2012). Also, various chemotherapeutic agents and other drugs such as sunitinib, doxorubicin, gemcitabine, bortezomib, cyclophosphamide, cisplatin, 5-fluorouracil, triploid, histone deacetylase inhibitors, smac mimetics, and a Bcl-2 inhibitor provided additional survival advantages with VSV treatment in different tumor models, suggesting that these treatment modalities are not incompatible (Ben Yebdri et al. 2013; Beug et al. 2014; Hastie, Besmer, et al. 2013; Jha et al. 2013; Leveille et al. 2011; Nguyên et al. 2008; Porosnicu et al. 2003; Samuel et al. 2013; Schache et al. 2009; Sung et al. 2008; Willmon et al. 2011; Yarde, Nace, et al. 2013, Yarde, Naik, et al. 2013). Alternatively, several compounds dubbed virus sensitizers were shown to increase viral replication and also prolong survival of tumor-bearing mice when administered in combination with VSV (Arulanandam, Batenchuk, Varette, et al. 2015; Diallo et al. 2010). Another strategy that was proven successful is the combination of different OVs. It was shown that coadministration of vaccinia virus, an OV that encodes immunoregulatory genes that can increase VSV replication, led to increased efficacy when compared with either virus alone (Le Boeuf et al. 2010). One factor that was identified as important for this effect is the protein B18R encoded by vaccinia virus. Accordingly, better efficacy was also observed using a VSV encoding B18R as a single agent (Le Bœuf et al. 2013).

Another approach is the combination of VSV with vaccination strategies. VSV is a well-studied vaccine vector and is recognized for its ability to stimulate both innate and adaptive immunity (McKenna et al. 2003). In a previous study, we demonstrated that the administration of VSV-infected B16F10 cells was a successful strategy to vaccinate mice against the same tumor type (Lemay et al. 2012). In another study using the L1210 leukemia cell line, we demonstrated that irradiated virus-infected cells could achieve the same results (Conrad et al. 2013). It was also demonstrated using the B16F10 tumor model that VSV could be used as a vaccination platform. Indeed, use of heterologous viruses that encoded the same tumor-associated antigen to prime and boost the antitumor immune response achieved a significant prolongation of survival (Bridle et al. 2010). Another means to stimulate the immune system is the use of immune checkpoint inhibitors. By depleting/blocking immunosuppressive regulatory T cells using antibodies in combination with VSV, measles virus, Newcastle disease virus, and reovirus, efficacy was improved (Engeland et al. 2014; Gao et al. 2009; Rajani et al. 2016; Zamarin et al. 2014).

Conclusion

With the first OV soon to be approved for use in patients upon the conclusion of a phase III study in advanced melanoma patients (Andtbacka et al. 2015) and various other clinical trial candidates, including VSV and Maraba virus, currently being evaluated, the field of OV therapy is rapidly evolving, and novel viruses and strategies are constantly being developed. The myriad in vivo tumor models and various techniques described herein allow for the validation of these novel treatments, facilitating the generation of preclinical safety data and evaluation of efficacy compared with currently available options.

Acknowledgments

This work was supported by the (TFF 122868), the Canadian Cancer Society Research Institute, the Ontario Institute for Cancer Research, the Canadian Institute for Health Research (CIHR), the Ottawa Regional Cancer Foundation, and the Ottawa Hospital Foundation. M.C.B.D and D.G.R were supported by the (MFI-140935 and GSD-121796). The animals in this study were used and euthanized humanely in accordance with the Guide for the Care and Use of Laboratory Animals.

References

  • Abraham N. 1999. Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. J Biol Chem 274:5953–5962. [PubMed]
  • Ahmed M, Cramer SD, Lyles DS Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses. 2004. Virology 330:34–49. [PubMed]
  • Ahmed M, Puckett S, Lyles DS 2010. Susceptibility of breast cancer cells to an oncolytic matrix (M) protein mutant of vesicular stomatitis virus. Cancer Gene Ther 17:883–892. [PMC free article] [PubMed]
  • Alajez NM, Mocanu JD, Krushel T, Bell JC, Liu F-F. 2012. Enhanced vesicular stomatitis virus (VSVΔ51) targeting of head and neck cancer in combination with radiation therapy or ZD6126 vascular disrupting agent. Cancer Cell Int 12:27. [PMC free article] [PubMed]
  • Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio S a JR, Behjati S, Biankin A V, Bignell GR, Bolli N, Borg A, Børresen-Dale A-L, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens J a, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Imielinsk M, Jäger N, Jones DTW, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott P a, Pajic M, Papaemmanuil E, Paradiso A, Pearson J V, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt ANJ, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR 2013. Signatures of mutational processes in human cancer. Nature 500:415–421. [PMC free article] [PubMed]
  • Altomonte J, Marozin S, De Toni EN, Rizzani A, Esposito I, Steiger K, Feuchtinger A, Hellerbrand C, Schmid RM, Ebert O 2013. Antifibrotic properties of transarterial oncolytic VSV therapy for hepatocellular carcinoma in rats with thioacetamide-induced liver fibrosis. Mol Ther 21:2032–2042. [PubMed]
  • Ammayappan A, Peng K-W, Russell SJ 2013. Characteristics of oncolytic vesicular stomatitis virus displaying tumor-targeting ligands. J Virol. 87:13543–13555. [PMC free article] [PubMed]
  • Andtbacka RHI, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin R 2015. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33:2780–2788. [PubMed]
  • Arulanandam R, Batenchuk C, Angarita FA, Ottolino-Perry K, Cousineau S, Mottashed A, Burgess E, Falls TJ, De Silva N, Tsang J, Howe GA, Bourgeois-Daigneault M-C, Conrad DP, Daneshmand M, Breitbach CJ, Kirn DH, Raptis L, Sad S, Atkins H, Huh MS, Diallo J-S, Lichty BD, Ilkow CS, Le Boeuf F, Addison CL, McCart JA, Bell JC 2015. VEGF-mediated induction of PRD1-BF1/Blimp1 expression sensitizes tumor vasculature to oncolytic virus infection. Cancer Cell 28:210–224. [PubMed]
  • Arulanandam R, Batenchuk C, Varette O, Zakaria C, Garcia V, Forbes NE, Davis C, Krishnan R, Karmacharya R, Cox J, Sinha A, Babawy A, Waite K, Weinstein E, Falls T, Chen A, Hamill J, De Silva N, Conrad DP, Atkins H, Garson K, Ilkow C, Kærn M, Vanderhyden B, Sonenberg N, Alain T, Le Boeuf F, Bell JC, Diallo J-S 2015. Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing. Nat Commun 6:6410. [PubMed]
  • Ayala-Breton C, Suksanpaisan L, Mader EK, Russell SJ, Peng K-W 2013. Amalgamating oncolytic viruses to enhance their safety, consolidate their killing mechanisms, and accelerate their spread. Mol Ther 21:1930–1937. [PubMed]
  • Balachandran S, Porosnicu M, Barber GN 2001. Oncolytic activity of vesicular stomatitis virus is effective against tumors exhibiting aberrant p53, Ras, or myc function and involves the induction of apoptosis. J Virol 75:3474–3479. [PMC free article] [PubMed]
  • Bell J, Roy D 2013. Cell carriers for oncolytic viruses: Current challenges and future directions. Oncolytic Virother 2:47.
  • Benton G, Kleinman HK, George J, Arnaoutova I 2011. Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int J Cancer 128:1751–1757. [PubMed]
  • Ben Yebdri F, Van Grevenynghe J, Tang VA, Goulet M-L, Wu JH, Stojdl DF, Hiscott J, Lin R 2013. Triptolide-mediated inhibition of interferon signaling enhances vesicular stomatitis virus-based oncolysis. Mol Ther 21:2043–2053. [PubMed]
  • Bergman I, Griffin JA, Gao Y, Whitaker-Dowling P 2007. Treatment of implanted mammary tumors with recombinant vesicular stomatitis virus targeted to Her2/neu. Int J Cancer 121:425–430. [PubMed]
  • Beug S t, Tange V a, LaCasse E, Cheung HH, Beauregard CE, Brun J, Nuyens JP, Earl N, St-Jean M, Holbrook J, Dastidar H, Mahoney DJ, Ilkow C, Le Boeuf F, Bell JC, Korneluk RG 2014. Smac mimetics and innate immune stimuli syngergize to promote tumor death. Nat Biotechnol 32:182–190. [PMC free article] [PubMed]
  • Biel NM, Lee JA, Sorg BS, Siemann DW 2014. Limitations of the dorsal skinfold window chamber model in evaluating anti-angiogenic therapy during early phase of angiogenesis. Vasc Cell 6:17. [PMC free article] [PubMed]
  • Blackham AU, Northrup S, Willingham M, D'Agostino RB, Lyles DS, Stewart JH 2012. Variation in susceptibility of human malignant melanomas to oncolytic vesicular stomatitis virus. Surgery 153:333–343. [PMC free article] [PubMed]
  • Blackham AU, Northrup SA, Willingham M, Sirintrapun J, Russell GB, Lyles DS, Stewart JH IV 2014. Molecular determinants of susceptibility to oncolytic vesicular stomatitis virus in pancreatic adenocarcinoma. J Surg Res 187:412–426. [PMC free article] [PubMed]
  • Breitbach CJ, Burke J, Jonker D, Stephenson J, Haas AR, Chow LQM, Nieva J, Hwang T-H, Moon A, Patt R, Pelusio A, Le Boeuf F, Burns J, Evgin L, De Silva N, Cvancic S, Robertson T, Je J-E, Lee Y-S, Parato K, Diallo J-S, Fenster A, Daneshmand M, Bell JC, Kirn DH 2011. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477:99–102. [PubMed]
  • Breitbach CJ, De Silva NS, Falls TJ, Aladl U, Evgin L, Paterson J, Sun YY, Roy DG, Rintoul JL, Daneshmand M, Parato K, Stanford MM, Lichty BD, Fenster A, Kirn D, Atkins H, Bell JC 2011. Targeting tumor vasculature with an oncolytic virus. Mol Ther 19:886–894. [PubMed]
  • Breitbach CJ, Paterson JM, Lemay CG, Falls TJ, McGuire A, Parato K a, Stojdl DF, Daneshmand M, Speth K, Kirn D, McCart JA, Atkins H, Bell JC 2007. Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow. Mol Ther 15:1686–1693. [PubMed]
  • Bridle BW, Stephenson KB, Boudreau JE, Koshy S, Kazdhan N, Pullenayegum E, Brunellière J, Bramson JL, Lichty BD, Wan Y 2010. Potentiating cancer immunotherapy using an oncolytic virus. Mol Ther 18:1430–1439. [PubMed]
  • Campbell JP, Merkel AR, Masood-Campbell SK, Elefteriou F, Sterling JA 2012. Models of bone metastasis. J Vis Exp e4260. [PMC free article] [PubMed]
  • Capo-chichi CD, Yeasky TM, Heiber JF, Wang Y, Barber GN, Xu XX 2010. Explicit targeting of transformed cells by VSV in ovarian epithelial tumor-bearing Wv mouse models. Gynecol Oncol 116:269–275. [PMC free article] [PubMed]
  • Carreno BM, Garbow JR, Kolar GR, Jackson EN, Engelbach JA, Becker-Hapak M, Carayannopoulos LN, Piwnica-Worms D, Linette GP 2009. Immunodeficient mouse strains display marked variability in growth of human melanoma lung metastases. Clin Cancer Res 15:3277–3286. [PMC free article] [PubMed]
  • Chang G, Xu S, Watanabe M, Jayakar HR, Whitt M, Gingrich JR 2010. Enhanced Oncolytic Activity of Vesicular Stomatitis Virus encoding SV5-F protein against prostate cancer. J Urol. 183:1611–1618. [PubMed]
  • Cheng J, Sauthoff H, Huang Y, Kutler DI, Bajwa S, Rom WN, Hay JG 2007. Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus. Mol Ther 15:1982–1990. [PubMed]
  • Chiavacci E, Rizzo M, Pitto L, Patella F, Evangelista M, Mariani L, Rainaldi G 2014. The zebrafish/tumor xenograft angiogenesis assay as a tool for screening anti-angiogenic miRNAs. Cytotechnology 67:969–975. [PMC free article] [PubMed]
  • Choi SYC, Lin D, Gout PW, Collins CC, Xu Y, Wang Y 2014. Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv Drug Deliv Rev 79–80:222–237. [PubMed]
  • Cronin M, Le Boeuf F, Murphy C, Roy DG, Falls T, Bell JC, Tangney M 2014. Bacterial-Mediated Knockdown of Tumor Resistance to an Oncolytic Virus Enhances Therapy. Mol Ther 22:1–10. [PubMed]
  • Clark AG, Vignjevic DM 2015. Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol 36:13–22. [PubMed]
  • Conrad DP, Tsang J, Maclean M, Diallo JS, Le Boeuf F, Lemay CG, Falls TJ, Parato KA, Bell JC, Atkins HL 2013. Leukemia cell-rhabdovirus vaccine: Personalized immunotherapy for acute lymphoblastic leukemia. Clin Cancer Res 19:3832–3843. [PubMed]
  • DeRose YS, Wang G, Lin Y-C, Bernard PS, Buys SS, Ebbert MTW, Factor R, Matsen C, Milash B a, Nelson E, Neumayer L, Randall RL, Stijleman IJ, Welm BE, Welm AL 2011. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med 17:1514–1520. [PMC free article] [PubMed]
  • Devaud C, Westwood J a, John LB, Flynn JK, Paquet-Fifield S, Duong CP, Yong CS, Pegram HJ, Stacker S a, Achen MG, Stewart TJ, Snyder L a, Teng MW, Smyth MJ, Darcy PK, Kershaw MH 2013. Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy. Mol Ther 22:18–27. [PubMed]
  • Diallo J-S, Le Boeuf F, Lai F, Cox J, Vaha-Koskela M, Abdelbary H, MacTavish H, Waite K, Falls T, Wang J, Brown R, Blanchard JE, Brown ED, Kirn DH, Hiscott J, Atkins H, Lichty BD, Bell JC 2010. A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers. Mol Ther 18:1123–1129. [PubMed]
  • Diallo J-S, Roy D, Abdelbary H, De Silva N, Bell JC 2011. Ex vivo infection of live tissue with oncolytic viruses. J Vis Exp 52:2854. [PubMed]
  • Ebert O, Harbaran S, Shinozaki K, Woo SLC 2005. Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice. Cancer Gene Ther 12:350–358. [PubMed]
  • Edge RE, Falls TJ, Brown CW, Lichty BD, Atkins H, Bell JC 2008. A let-7 MicroRNA-sensitive vesicular stomatitis virus demonstrates tumor-specific replication. Mol Ther 16:1437–1443. [PubMed]
  • Eisenstein S, Coakley B a., Briley-Saebo K, Ma G, Chen HM, Meseck M, Ward S, Divino C, Woo S, Chen SH, Pan PY 2013. Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy. Cancer Res 73:5003–5015. [PMC free article] [PubMed]
  • Engeland CE, Grossardt C, Veinalde R, Bossow S, Lutz D, Kaufmann JK, Shevchenko I, Umansky V, Nettelbeck DM, Weichert W, Jäger D, von Kalle C, Ungerechts G 2014. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol Ther 22:1949–1959. [PubMed]
  • Evgin L, Acuna S a, Tanese de Souza C, Marguerie M, Lemay CG, Ilkow CS, Findlay CS, Falls T, Parato K a, Hanwell D, Goldstein A, Lopez R, Lafrance S, Breitbach CJ, Kirn D, Atkins H, Auer RC, Thurman JM, Stahl GL, Lambris JD, Bell JC, McCart JA 2015. Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques. Mol Ther 23:1066–1076. [PubMed]
  • Feitsma H, Cuppen E 2008. Zebrafish as a cancer model. 6:685–694. [PubMed]
  • Ferguson MS, Lemoine NR, Wang Y 2012. Systemic delivery of oncolytic viruses: Hopes and hurdles. Adv Virol 2012:805629. [PMC free article] [PubMed]
  • Fernandez M, Porosnicu M, Markovic D, Barber GN 2002. Genetically engineered vesicular stomatitis virus in gene therapy: Application for treatment of malignant disease. Society 76:895–904. [PMC free article] [PubMed]
  • Fisher K. 2006. Striking out at disseminated metastases: The systemic delivery of oncolytic viruses. Curr Opin Mol Ther 8:301–313. [PubMed]
  • Frese KK, Tuveson DA 2007. Maximizing mouse cancer models. Nat Rev Cancer 7:645–658. [PubMed]
  • Fridman R, Benton G, Aranoutova I, Kleinman HK, Bonfil RD 2012. Increased initiation and growth of tumor cell lines, cancer stem cells and biopsy material in mice using basement membrane matrix protein (Cultrex or Matrigel) co-injection. Nat Protoc 7:1138–1144. [PubMed]
  • Galivo F, Diaz RM, Thanarajasingam U, Jevremovic D, Wongthida P, Thompson J, Kottke T, Barber GN, Melcher A, Vile RG 2010. Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. Hum Gene Ther 21:439–450. [PMC free article] [PubMed]
  • Ganesh S, Gonzalez-Edick M, Gibbons D, Van Roey M, Jooss K 2008. Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models. Clin Cancer Res 14:3933–3941. [PubMed]
  • Gao Y, Whitaker-Dowling P, Griffin JA, Barmada MA, Bergman I 2009. Recombinant vesicular stomatitis virus targeted to Her2/neu combined with anti-CTLA4 antibody eliminates implanted mammary tumors. Cancer Gene Ther 16:44–52. [PubMed]
  • Garijo R, Hernández-Alonso P, Rivas C, Diallo JS, Sanjuán R 2014. Experimental evolution of an oncolytic vesicular stomatitis virus with increased selectivity for p53-deficient cells. PLoS One 9:1–8. [PMC free article] [PubMed]
  • Goel A, Carlson SK, Classic KL, Greiner S, Naik S, Power AT, Bell JC, Russell SJ 2007. Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV(??51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene. Blood 110:2342–2350. [PubMed]
  • Hanahan D. 2000. The hallmarks of cancer. Cell 100:57–70. [PubMed]
  • Hastie E, Besmer DM, Shah NR, Murphy AM, Moerdyk-Schauwecker M, Molestina C, Roy LD, Curry JM, Mukherjee P, Grdzelishvili VZ 2013. Oncolytic vesicular stomatitis virus in an immunocompetent model of MUC1-positive or MUC1-null pancreatic ductal adenocarcinoma. J Virol 87:10283–10294. [PMC free article] [PubMed]
  • Hastie E, Cataldi M, Marriott I, Grdzelishvili VZ 2013. Understanding and altering cell tropism of vesicular stomatitis virus. Virus Res 176:16–32. [PMC free article] [PubMed]
  • Hastie E, Grdzelishvili VZ 2012. Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer. J Gen Virol 93:2529–2545. [PMC free article] [PubMed]
  • Heiber JF, Barber GN 2011. Vesicular Stomatitis Virus Expressing Tumor Suppressor p53 Is a Highly Attenuated, Potent Oncolytic Agent. J Virol. 85:10440–10450. [PMC free article] [PubMed]
  • Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim ho yeong, Chung hyun cheol, Kim chang won, Burke J, Lencioni R, Hickman T, Moon A, Lee yeon sook, Kim mi kyeong, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee B, Patt R, Hwang T, Kirn Dh 2013. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 19:329–336. [PMC free article] [PubMed]
  • Hirasawa K, Nishikawa SG, Norman KL, Coffey MC, Thompson BG, Yoon C, Waisman DM, Lee PWK 2003. Systemic reovirus therapy of metastatic cancer in immune-competent mice systemic reovirus therapy of metastatic cancer in immune-competent mice 1. Cancer Res 63:348–353. [PubMed]
  • Hoffman RM. 2015. Patient-derived orthotopic xenografts: Better mimic of metastasis than subcutaneous xenografts. Nat Rev Cancer 15:451–452. [PubMed]
  • Huneycutt BS, Bi Z, Aoki CJ, Reiss CS 1993. Central neuropathogenesis of vesicular stomatitis virus infection of immunodeficient mice. J Virol 67:6698–6706. [PMC free article] [PubMed]
  • Ilett EJ, Bárcena M, Errington-Mais F, Griffin S, Harrington KJ, Pandha HS, Coffey M, Selby PJ, Limpens RWAL, Mommaas M, Hoeben RC, Vile RG, Melcher AA 2011. Internalization of oncolytic reovirus by human dendritic cell carriers protects the virus from neutralization. Clin Cancer Res 17:2767–2776. [PMC free article] [PubMed]
  • Ilkow CS, Marguerie M, Batenchuk C, Mayer J, Ben Neriah D, Cousineau S, Falls T, Jennings V a, Boileau M, Bellamy D, Bastin D, de Souza CT, Alkayyal A, Zhang J, Le Boeuf F, Arulanandam R, Stubbert L, Sampath P, Thorne SH, Paramanthan P, Chatterjee A, Strieter RM, Burdick M, Addison CL, Stojdl DF, Atkins HL, Auer RC, Diallo J-S, Lichty BD, Bell JC 2015. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat Med 21:530–536. [PubMed]
  • Jain RK. 1990. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev 9:253–266. [PubMed]
  • Janelle V, Langlois M-P, Lapierre P, Charpentier T, Poliquin L, Lamarre A 2014. The strength of the T Cell response against a surrogate tumor antigen induced by oncolytic VSV therapy does not correlate with tumor control. Mol Ther 22:1198–1210. [PubMed]
  • Jayachandran A, McKeown SJ, Woods BL, Prithviraj P, Cebon J 2015. Embryonic chicken transplantation is a promising model for studying the invasive behavior of melanoma cells. Front Oncol 5:1–7. [PMC free article] [PubMed]
  • Jenks N, Myers R, Greiner SM, Thompson J, Mader EK, Greenslade A, Griesmann GE, Federspiel MJ, Rakela J, Borad MJ, Vile RG, Barber GN, Meier TR, Blanco MC, Carlson SK, Russell SJ, Peng K-W 2010. Safety studies on intrahepatic or intratumoral injection of oncolytic vesicular stomatitis virus expressing interferon-beta in rodents and nonhuman primates. Hum Gene Ther 21:451–462. [PMC free article] [PubMed]
  • Jha BK, Dong B, Nguyen CT, Polyakova I, Silverman RH 2013. Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy. Mol Ther 21:1749–1757. [PubMed]
  • Jin Z, Jin M, Jiang C, Yin X, Jin S, Quan X, Gao Z 2014. Evaluation of doxorubicin-loaded pH-sensitive polymeric micelle release from tumor blood vessels and anticancer efficacy using a dorsal skin-fold window chamber model. Acta Pharmacol Sin 35:839–845. [PMC free article] [PubMed]
  • Johnson JE, Nasar F, Coleman JW, Price RE, Javadian A, Draper K, Lee M, Reilly PA, Clarke DK, Hendry RM, Udem SA 2007. Neurovirulence properties of recombinant vesicular stomatitis virus vectors in non-human primates. Virology 360:36–49. [PMC free article] [PubMed]
  • Kato M, Watabe K, Tsujii M, Funahashi T, Shimomura I, Takehara T 2014. Adiponectin inhibits murine pancreatic cancer growth. Dig Dis Sci 59:1192–1196. [PubMed]
  • Kelly EJ, Hadac EM, Greiner S, Russell SJ 2008. Engineering microRNA responsiveness to decrease virus pathogenicity. Nat Med 14:1278–1283. [PubMed]
  • Kim J.-H, Lee Y-S, Kim H, Huang J-H, Yoon A-R, Yun C-O 2006. Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst 98:1482–1493. [PubMed]
  • Kim MP, Evans DB, Wang H, Abbruzzese JL, Fleming JB, Gallick GE 2009. Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat Protoc 4:1670–1680. [PMC free article] [PubMed]
  • Kim S, Roopra A, Alexander CM 2012. A phenotypic mouse model of basaloid breast tumors. PLoS One 7:1–14. [PMC free article] [PubMed]
  • Kottke T, Diaz RM, Kaluza K, Pulido J, Galivo F, Wongthida P, Thompson J, Willmon C, Barber GN, Chester J, Selby P, Strome S, Harrington K, Melcher A, Vile RG 2008. Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer. Mol Ther 16:1910–1918. [PMC free article] [PubMed]
  • Kurisetty VVS, Heiber J, Myers R, Pereira GS, Goodwin JW, Federspiel MJ, Russell SJ, Peng KW, Barber G, Merchan JR 2014. Preclinical safety and activity of recombinant VSV-IFN-β in an immunocompetent model of squamous cell carcinoma of the head and neck. Head Neck 36:1619–1627. [PMC free article] [PubMed]
  • Kuriyama N, Kuriyama H, Julin CM, Lamborn K, Israel MA 2000. Pretreatment with protease is a useful experimental strategy for enhancing adenovirus-mediated cancer gene therapy. Hum Gene Ther 11:2219–2230. [PubMed]
  • Kuzmin IV, Novella IS, Dietzgen RG, Padhi A, Rupprecht CE 2009. The rhabdoviruses: Biodiversity, phylogenetics, and evolution. Infect Genet Evol 9:541–553. [PubMed]
  • LeBlanc AK, Naik S, Galyon GD, Jenks N, Steele M, Peng K-W, Federspiel MJ, Donnell R, Russell SJ 2013. Safety studies on intravenous administration of oncolytic recombinant vesicular stomatitis virus in purpose-bred beagle dogs. Hum Gene Ther Clin Dev 24:174–181. [PMC free article] [PubMed]
  • Le Bœuf F, Batenchuk C, Vähä-Koskela M, Breton S, Roy D, Lemay C, Cox J, Abdelbary H, Falls T, Waghray G, Atkins H, Stojdl D, Diallo J-S, Kærn M, Bell JC 2013. Model-based rational design of an oncolytic virus with improved therapeutic potential. Nat Commun 4:1974. [PubMed]
  • Le Boeuf F, Diallo J-S, McCart JA, Thorne S, Falls T, Stanford M, Kanji F, Auer R, Brown CW, Lichty BD, Parato K, Atkins H, Kirn D, Bell JC 2010. Synergistic interaction between oncolytic viruses augments tumor killing. Mol Ther 18:888–895. [PubMed]
  • Le Boeuf F, Niknejad N, Wang J, Auer R, Weberpals JI, Bell JC, Dimitroulakos J 2012. Sensitivity of cervical carcinoma cells to vesicular stomatitis virus-induced oncolysis: Potential role of human papilloma virus infection. Int J Cancer 131:E204–E215. [PubMed]
  • Lemay CG, Rintoul JL, Kus A, Paterson JM, Garcia V, Falls TJ, Ferreira L, Bridle BW, Conrad DP, Tang V a, Diallo J-S, Arulanandam R, Le Boeuf F, Garson K, Vanderhyden BC, Stojdl DF, Lichty BD, Atkins HL, Parato K a, Bell JC, Auer RC 2012. Harnessing oncolytic virus-mediated antitumor immunity in an infected cell vaccine. Mol Ther 20:1791–1799. [PubMed]
  • Leveille S, Samuel S, Goulet M-L, Hiscott J 2011. Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy. Cancer Gene Ther 18:435–443. [PubMed]
  • Lichty BD, Breitbach CJ, Stojdl DF, Bell JC 2014. Going viral with cancer immunotherapy. Nat Rev Cancer 14:559–567. [PubMed]
  • Lichty BD, Power AT, Stojdl DF, Bell JC 2004. Vesicular stomatitis virus: Re-inventing the bullet. Trends Mol Med 10:210–216. [PubMed]
  • Liu YP, Steele MB, Suksanpaisan L, Federspiel MJ, Russell SJ, Peng KW, Bakkum-Gamez JN 2014. Oncolytic measles and vesicular stomatitis virotherapy for endometrial cancer. Gynecol Oncol. 132:194–202. [PMC free article] [PubMed]
  • Lun X, Senger DL, Alain T, Oprea A, Parato K, Stojdl D, Lichty B, Power A, Johnston RN, Hamilton M, Parney I, Bell JC, Forsyth P 2006. Effects of intravenously administered recombinant vesicular stomatitis virus (VSVM51) on multifocal and invasive gliomas. J Natl Cancer Inst. 98:1546–1557. [PubMed]
  • Mahoney DJ, Stojdl DF 2013. Molecular pathways: Multimodal cancer-killing mechanisms employed by oncolytic vesiculoviruses. Clin Cancer Res 19:758–763. [PubMed]
  • Matsuo H, Ryu M, Nagata A, Uchida T, Kawakami JI, Yamamoto K, Iga T, Sawada Y 1998. Neurotoxicodynamics of the interaction between ciprofloxacin and foscarnet in mice. Antimicrob Agents Chemother 42:691–694. [PMC free article] [PubMed]
  • McCart JA, Ward JM, Lee J, Hu Y, Alexander HR, Libutti SK, Moss B, Bartlett DL 2001. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res 61:8751–8757. [PubMed]
  • McKee TD, Grandi P, Mok W, Alexandrakis G, Insin N, Zimmer JP, Bawendi MG, Boucher Y, Breakefield XO, Jain RK 2006. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res 66:2509–2513. [PubMed]
  • McKenna PM, McGettigan JP, Pomerantz RJ, Dietzschold B, Schnell MJ 2003. Recombinant rhabdoviruses as potential vaccines for HIV-1 and other diseases. Curr HIV Res 1:229–237. [PubMed]
  • Meraz M a, White JM, Sheehan KC, Bach E a, Rodig SJ, Dighe a S, Kaplan DH, Riley JK, Greenlund a C, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M, Schreiber RD 1996. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431–442. [PubMed]
  • Miller JM, Bidula SM, Jensen TM, Reiss CS 2010. Vesicular stomatitis virus modified with single chain IL-23 exhibits oncolytic activity against tumor cells in vitro and in vivo. Int. J. Infereron. Cytokine Mediator Res. 2:63–72. [PMC free article] [PubMed]
  • Mirandola L, Yu Y, Chui K, Jenkins MR, Cobos E, John CM, Chiriva-Internati M 2011. Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma. PLoS One 6:21811. [PMC free article] [PubMed]
  • Moussavi M, Fazli L, Tearle H, Guo Y, Cox M, Bell J, Ong C, Jia W, Rennie PS 2010. Oncolysis of prostate cancers induced by vesicular stomatitis virus in PTEN knockout mice. Cancer Res 70:1367–1376. [PubMed]
  • Moussavi M, Tearle H, Fazli L, Bell JC, Jia W, Rennie PS 2013. Targeting and killing of metastatic cells in the transgenic adenocarcinoma of mouse prostate model with vesicular stomatitis virus. Mol Ther 21:842–848. [PubMed]
  • Muik A, Dold C, Geiß Y, Volk A, Werbizki M, Dietrich U, von Laer D 2012. Semireplication-competent vesicular stomatitis virus as a novel platform for oncolytic virotherapy. J Mol Med (Berl). 90:959–970. [PMC free article] [PubMed]
  • Muik A, Stubbert LJ, Jahedi RZ, Geib Y, Kimpel J, Dold C, Tober R, Volk A, Klein S, Dietrich U, Yadollahi B, Falls T, Miletic H, Stojdl D, Bell JC, Von Laer D 2014. Re-engineering vesicular stomatitis virus to abrogate neurotoxicity, circumvent humoral immunity, and enhance oncolytic potency. Cancer Res 74:3567–3578. [PubMed]
  • Muller U, Steinhoff U, Reis LFL, Hemmi S, Paviovic J, Zinkernagel RM, Aguet M 1994. Functional role of type I and type 11 in antiviral interferons defense. 264:1918–1921. [PubMed]
  • Murphy M, Besmer DM, Moerdyk-Schauwecker M, Moestl N, Ornelles D, Mukherjee P, Grdzelishvili VZ 2012. Vesicular Stomatitis Virus as an oncolytic agent against pancreatic ductal adenocarcinoma. J Virol. 86:3073–3087. [PMC free article] [PubMed]
  • Naik S, Nace R, Barber GN, Russell SJ 2012. Potent systemic therapy of multiple myeloma utilizing oncolytic vesicular stomatitis virus coding for interferon-β. Cancer Gene Ther. 19:443–450. [PMC free article] [PubMed]
  • Nanni P, De Giovanni C, Lollini PL, Nicoletti G, Prodi G 1983. TS/A: A new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma. Clin Exp Metastasis 1:373–380. [PubMed]
  • Nassar D, Latil M, Boeckx B, Lambrechts D, Blanpain C 2015. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat Med 21:946–954. [PubMed]
  • Nguyên TL-A, Abdelbary H, Arguello M, Breitbach C, Leveille S, Diallo J-S, Yasmeen A, Bismar TA, Kirn D, Falls T, Snoulten VE, Vanderhyden BC, Werier J, Atkins H, Vähä-Koskela MJ V, Stojdl DF, Bell JC, Hiscott J 2008. Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis. Proc Natl Acad Sci U S A 105:14981–14986. [PubMed]
  • Nilaver G, Muldoon LL, Kroll RA, Pagel MA, Breakefield XO, Davidson BL, Neuwelt EA 1995. Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption. Proc Natl Acad Sci U S A 92:9829–9833. [PubMed]
  • Obuchi M, Fernandez M, Barber GN 2003. Development of recombinant vesicular stomatitis viruses that exploit defects in host defense to augment specific oncolytic activity. J Virol 77:8843–8856. [PMC free article] [PubMed]
  • Olive KP, Tuveson DA 2006. The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin Cancer Res 12:5277–5287. [PubMed]
  • Ottolino-Perry K, Diallo J-S, Lichty BD, Bell JC, McCart JA 2010. Intelligent design: Combination therapy with oncolytic viruses. Mol Ther 18:251–263. [PubMed]
  • Ozduman K, Wollmann G, Piepmeier JM, van den Pol AN 2008. Systemic vesicular stomatitis virus selectively destroys multifocal glioma and metastatic carcinoma in brain. J Neurosci 28:1882–1893. [PubMed]
  • Paglino JC, van den Pol AN 2011. Vesicular stomatitis virus has extensive oncolytic activity against human sarcomas: rare resistance is overcome by blocking interferon pathways. J Virol. 85:9346–9358. [PMC free article] [PubMed]
  • Palmer GM, Fontanella AN, Shan S, Dewhirst MW 2012. High-resolution in vivo imaging of fluorescent proteins using window chamber models. Methods Mol Biol 872:31–50. [PMC free article] [PubMed]
  • Porosnicu M, Mian A, Barber GN 2003. The oncolytic effect of recombinant vesicular stomatitis virus is enhanced by expression of the fusion cytosine deaminase/uracil phosphoribosyltransferase suicide gene. Cancer Res 63:8366–8376. [PubMed]
  • Power AT, Wang J, Falls TJ, Paterson JM, Parato KA, Lichty BD, Stojdl DF, Forsyth PAJ, Atkins H, Bell JC 2007. Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity. Mol Ther 15:123–130. [PubMed]
  • Pulaski BA, Ostrand-Rosenberg S 2001. Mouse 4T1 Breast Tumor Model. Current Protocols in Immunology. New Jersey: Wiley Online Library. [PubMed]
  • Qiao J, Kottke T, Willmon C, Galivo F, Wongthida P, Diaz RM, Thompson J, Ryno P, Barber GN, Chester J, Selby P, Harrington K, Melcher A, Vile RG 2008. Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy. Nat Med 14:37–44. [PubMed]
  • Qiao J, Moreno J, Sanchez-Perez L, Kottke T, Thompson J, Caruso M, Diaz RM, Vile R 2006. VSV-G pseudotyped, MuLV-based, semi-replication-competent retrovirus for cancer treatment. Gene Ther 13:1457–1470. [PubMed]
  • Rajani K, Parrish C, Kottke T, Thompson J, Zaidi S, Ilett L, Shim KG, Diaz R-M, Pandha H, Harrington K, Coffey M, Melcher A, Vile R 2016. Combination therapy with reovirus and anti-PD-1 blockade controls tumor growth through innate and adaptive immune responses. Mol Ther 24:166–174. [PubMed]
  • Rajaram N, Frees AE, Fontanella AN, Zhong J, Hansen K, Dewhirst MW, Ramanujam N 2013. Delivery rate affects uptake of a fluorescent glucose analog in murine metastatic breast cancer. PLoS One 8:76524. [PMC free article] [PubMed]
  • Rintoul JL, Lemay CG, Tai L-H, Stanford MM, Falls TJ, de Souza CT, Bridle BW, Daneshmand M, Ohashi PS, Wan Y, Lichty BD, Mercer AA, Auer RC, Atkins HL, Bell JC 2012. ORFV: A novel oncolytic and immune stimulating parapoxvirus therapeutic. Mol Ther 20:1148–1157. [PubMed]
  • Rommelfanger DM, Wongthida P, Diaz RM, Kaluza KM, Thompson JM, Kottke TJ, Vile RG 2012. Systemic combination virotherapy for melanoma with tumor antigen-expressing vesicular stomatitis virus and adoptive T-cell transfer. Cancer Res 72:4753–4764. [PMC free article] [PubMed]
  • Rötzschke O, Falk K, Stevanović S, Jung G, Walden P, Rammensee HG 1991. Exact prediction of a natural T cell epitope. Eur J Immunol 21:2891–2894. [PubMed]
  • Roy DG, Power AT, Bourgeois-Daigneault MC, Falls T, Ferreira L, Stern A, Tanese de Souza C, McCart JA, Stojdl DF, Lichty BD, Atkins H, Auer RC, Bell JC, Le Boeuf F 2015. Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy. J Control Release 220:210–221. [PubMed]
  • Samuel S, Beljanski V, Van Grevenynghe J, Richards S, Ben Yebdri F, He Z, Nichols C, Belgnaoui SM, Steel C, Goulet M-L, Shamy A, Brown D, Abesada G, Haddad EK, Hiscott J 2013. BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis. Mol Ther 21:1413–1423. [PubMed]
  • Schache P, Gürlevik E, Strüver N, Woller N, Malek N, Zender L, Manns M, Wirth T, Kühnel F, Kubicka S 2009. VSV virotherapy improves chemotherapy by triggering apoptosis due to proteasomal degradation of Mcl-1. Gene Ther 16:849–861. [PubMed]
  • Sharpless NE, Depinho RA 2006. The mighty mouse: Genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 5:741–754. [PubMed]
  • Shashkova EV, Doronin K, Senac JS, Barry MA 2008. Macrophage depletion combined with anticoagulant therapy increases therapeutic window of systemic treatment with oncolytic adenovirus. Cancer Res 68:5896–5904. [PubMed]
  • Shevchenko I, Karakhanova S, Soltek S, Link J, Bayry J, Werner J, Umansky V, Bazhin AV 2013. Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer. Int J Cancer 133:98–107. [PubMed]
  • Shi W, Tang Q, Chen X, Cheng P, Jiang P, Jing X, Chen X, Chen P, Wang Y, Wei Y, Wen Y 2009. Antitumor and antimetastatic activities of vesicular stomatitis virus matrix protein in a murine model of breast cancer. J Mol Med 87:493–506. [PubMed]
  • Shibata MA, Morimoto J, Akamatsu K, Otsuki Y 2008. Antimetastatic effect of suicide gene therapy for mouse mammary cancers requires T-cell-mediated immune responses. Med Mol Morphol 41:34–43. [PubMed]
  • Simanainen U, Ryan T, Li D, Suarez FG, Gao YR, Watson G, Wang Y, Handelsman DJ 2015. Androgen receptor actions modify skin structure and chemical carcinogen-induced skin cancer susceptibility in mice. Horm Cancer 6:45–53. [PubMed]
  • Simeoni M, De Nicolao G, Magni P, Rocchetti M, Poggesi I 2013. Modeling of human tumor xenografts and dose rationale in oncology. Drug Discov Today Technol 10:e365–e372. [PubMed]
  • Singh PK, Doley J, Kumar GR, Sahoo AP, Tiwari AK 2012. Oncolytic viruses & their specific targeting to tumour cells. Indian J Med Res 136:571–584. [PMC free article] [PubMed]
  • Stephenson KB, Barra NG, Davies E, Ashkar AA, Lichty BD 2012. Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity. Cancer Gene Ther 19:238–246. [PubMed]
  • Stojdl DF, Abraham N, Knowles S, Marius R, Brasey A, Lichty BD, Brown EG, Sonenberg N, Bell JC 2000. The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. J Virol 74:9580–9585. [PMC free article] [PubMed]
  • Stojdl DF, Lichty B, Knowles S, Marius R, Atkins H, Sonenberg N, Bell JC 2000. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 6:821–825. [PubMed]
  • Stojdl DF, Lichty BD, TenOever BR, Paterson JM, Power AT, Knowles S, Marius R, Reynard J, Poliquin L, Atkins H, Brown EG, Durbin RK, Durbin JE, Hiscott J, Bell JC 2003. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 4:263–275. [PubMed]
  • Sung C-K, Choi B, Wanna G, Genden EM, Woo SLC, Shin EJ 2008. Combined VSV oncolytic virus and chemotherapy for squamous cell carcinoma. Laryngoscope 118:237–242. [PubMed]
  • Tesfay MZ, Kirk AC, Hadac EM, Griesmann GE, Federspiel MJ, Barber GN, Henry SM, Peng K-W, Russell SJ 2013. PEGylation of vesicular stomatitis virus extends virus persistence in blood circulation of passively immunized mice. J Virol. 87:3752–3759. [PMC free article] [PubMed]
  • Thomsen AR, Nansen A, Andersen C, Johansen J, Marker O, Christensen JP 1997. Cooperation of B cells and T cells is required for survival of mice infected with vesicular stomatitis virus. Int Immunol 9:1757–1766. [PubMed]
  • Tracz A, Mastri M, Lee CR, Pili R, Ebos JML 2014. Modeling spontaneous metastatic renal cell carcinoma (mRCC) in mice following nephrectomy. J Vis Exp e51485–e51485. [PubMed]
  • van den Pol AN, Davis JN 2013. Highly attenuated recombinant vesicular stomatitis virus VSV-12'GFP displays immunogenic and oncolytic activity. J Virol. 87:1019–1034. [PMC free article] [PubMed]
  • Vanharanta S, Massagué J 2013. Origins of metastatic traits. Cancer Cell 24:410–421. [PMC free article] [PubMed]
  • Vonlaufen A, Joshi S, Qu C, Phillips P a., Xu Z, Parker NR, Toi CS, Pirola RC, Wilson JS, Goldstein D, Apte M V 2008. Pancreatic stellate cells: Partners in crime with pancreatic cancer cells. Cancer Res 68:2085–2093. [PubMed]
  • Warren S, Gates O 1963. The fate of intravenously injected tumor cells. Am J Cancer 27:485–492.
  • Westcott PMK, Halliwill KD, To MD, Rashid M, Rust AG, Keane TM, Delrosario R, Jen K-Y, Gurley KE, Kemp CJ, Fredlund E, Quigley DA, Adams DJ, Balmain A 2014. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517:489–492. [PMC free article] [PubMed]
  • Willmon C, Diaz RM, Wongthida P, Galivo F, Kottke T, Thompson J, Albelda S, Harrington K, Melcher A, Vile R 2011. Vesicular stomatitis virus-induced immune suppressor cells generate antagonism between intratumoral oncolytic virus and cyclophosphamide. Mol Ther 19:140–149. [PubMed]
  • Willmon C, Harrington K, Kottke T, Prestwich R, Melcher A, Vile R 2009. Cell carriers for oncolytic viruses: Fed Ex for cancer therapy. Mol Ther 17:1667–1676. [PubMed]
  • Willmon CL, Saloura V, Fridlender ZG, Wongthida P, Diaz RM, Thompson J, Kottke T, Federspiel M, Barber G, Albelda SM, Vile RG 2009. Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. Cancer Res 69:7713–7720. [PMC free article] [PubMed]
  • Wollmann G, Drokhlyansky E, Cepko C, van den Pol AN 2015. Lassa-VSV chimeric virus safely destroys brain tumors. J Virol 89:6711–6724. [PMC free article] [PubMed]
  • Wollmann G, Rogulin V, Simon I, Rose JK, van den Pol AN 2010. Some attenuated variants of vesicular stomatitis virus show enhanced oncolytic activity against human glioblastoma cells relative to normal brain cells. J Virol 84:1563–1573. [PMC free article] [PubMed]
  • Wongthida P, Diaz RM, Galivo F, Kottke T, Thompson J, Melcher A, Vile R 2011. VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. Mol Ther 19:150–158. [PubMed]
  • Wongthida P, Diaz RM, Galivo F, Kottke T, Thompson J, Pulido J, Pavelko K, Pease L, Melcher A, Vile R 2010. Type III IFN interleukin-28 mediates the antitumor efficacy of oncolytic virus VSV in immune-competent mouse models of cancer. Cancer Res 70:4539–4549. [PMC free article] [PubMed]
  • Wongthida P, Diaz RM, Pulido C, Rommelfanger D, Galivo F, Kaluza K, Kottke T, Thompson J, Melcher A, Vile R 2011. Activating systemic T-Cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus. Hum Gene Ther 22:1343–1353. [PMC free article] [PubMed]
  • Wu L, Huang T, Meseck M, Altomonte J, Ebert O, Shinozaki K, García-Sastre A, Fallon J, Mandeli J, Woo SLC 2008. rVSV(M Delta 51)-M3 is an effective and safe oncolytic virus for cancer therapy. Hum Gene Ther 19:635–647. [PMC free article] [PubMed]
  • Yarde DN, Nace RA, Russell SJ 2013. Oncolytic vesicular stomatitis virus and bortezomib are antagonistic against myeloma cells in vitro but have additive anti-myeloma activity in vivo. Exp Hematol 41:1038–1049. [PMC free article] [PubMed]
  • Yarde DN, Naik S, Nace RA, Peng K-W, Federspiel MJ, Russell SJ 2013. Meningeal myeloma deposits adversely impact the therapeutic index of an oncolytic VSV. Cancer Gene Ther 20:616–621. [PMC free article] [PubMed]
  • Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, Merghoub T, Wolchok JD, Allison JP 2014. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 6:226ra32. [PMC free article] [PubMed]
  • Zeyaullah M, Patro M, Ahmad I, Ibraheem K, Sultan P, Nehal M, Ali A 2012. Oncolytic viruses in the treatment of cancer: A review of current strategies. Pathol Oncol Res 18:771–781. [PubMed]
  • Zhang J, Tai L-H, Ilkow CS, Alkayyal AA, Ananth AA, de Souza CT, Wang J, Sahi S, Ly L, Lefebvre C, Falls TJ, Stephenson KB, Mahmoud AB, Makrigiannis AP, Lichty BD, Bell JC, Stojdl DF, Auer RC 2014. Maraba MG1 virus enhances natural killer cell function via conventional dendritic cells to reduce postoperative metastatic disease. Mol Ther 22:1320–1332. [PubMed]
  • Zhao X, Huang S, Luo H, Wan X, Gui Y, Li J, Wu D 2014. Evaluation of vesicular stomatitis virus mutant as an oncolytic agent against prostate cancer. Int J Clin Exp Med 7:1204–1213. [PMC free article] [PubMed]

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