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Cancer affects nearly 15 of every 100,000 children in the United States, and although survival rates have improved greatly over the past 30 y owing to cooperative trials and advances in surgical techniques, chemotherapy, and radiotherapy regimens, a significant subset of children, approximately 20%, succumb to their disease (1). Oncolytic viral therapy with or without gene therapy may be used to target cancer stem cells (CSCs). HSV is a double-stranded, enveloped DNA cytolytic virus that has shown promise in treating a variety of pediatric malignancies including brain tumors, neuroblastoma, and sarcomas (11).
Recent research has examined the ability of mutant HSVs to kill CSCs from pediatric neural tumors (Table 3 summarizes studies using oncolytic viruses to target pediatric CSCs). Another approach to targeting CSCs with engineered HSV is to disrupt the microenvironment through specific proteins produced during viral replication to supplement the oncolytic effects of the virus. Adenovirus is a nonenveloped, nonintegrated double-stranded DNA virus in the Adenoviridae family that has been studied extensively as a novel, oncolytic therapeutic. Reovirus (respiratory enteric orphan virus) is a nonenveloped, double-stranded, segmented RNA virus that has shown potential as an oncolytic, targeted agent.
SVV is a recently discovered single-stranded, nonenveloped, nonintegrating RNA virus in the family Picornaviridae. VV is a double-stranded, enveloped DNA virus in the poxvirus family that was first used as a vaccination against smallpox and more recently has been attenuated for use as a cancer therapeutic. These CSCs are thought to be responsible for tumorigenesis and tumor maintenance, aggressiveness, and recurrence due to inherent resistance to current treatment modalities such as chemotherapy and radiation. We showed that pediatric GBM xenograft D456MG contains CSCs marked by expression of CD133 (prominin-1), a transmembrane protein with uncertain biological function expressed on the surface of neuronal and hematopoietic stem cells and CSCs in a variety of malignancies (23).
Whereas wild-type adenoviruses can infect both dividing and nondividing cells and cause respiratory, ophthalmic, or gastrointestinal illnesses in humans, attenuated conditionally replicative adenoviruses (CRAds) can target cancer cells with few side effects. The conditionally replication-competent virus does not cause disease in humans but has potent cytolytic activity in some cancer cell types.
Oncolytic virotherapy offers a novel, targeted approach for eradicating pediatric CSCs using mechanisms of cell killing that differ from conventional therapies. In the past, new treatment regimens have focused on increasing the dose of current therapies or combining multiple cytotoxic agents for patients with high-risk disease; however, current regimens already approach the upper limits of tolerability.
Matrix metalloproteinases are a group of endopeptidases that degrade the extracellular matrix and thus play a critical role in the tumor niche by permitting angiogenesis and invasion. Deletions in immediate-early (E1A) or early (E1B) adenovirus genes result in attenuated mutants that cannot bind normal cellular proteins that drive gene expression initiating and maintaining cellular proliferation needed for productive virus infection (34). It is limited by cellular activation of protein kinase R, which subsequently phosphorylates eukaryotic initiation factor 2α, resulting in inhibition of viral gene translation and an ineffective infection in normal cells (52). The mechanism by which SVV produces a productive infection in cancer cells has not been fully elucidated; however, cell-surface receptor interactions with the virus appear to be an important component, and viral replication is at least partially mediated through autophagy (57,58). The TK-deleted virus requires thymidine triphosphate for DNA synthesis, which is provided by dividing cells, thus leading to preferential replication in dividing cells and tumor cell specificity.
Moreover, oncolytic viruses have the ability to target specific features of CSCs such as cell-surface proteins, transcription factors, and the CSC microenvironment. Therefore, simply increasing the dose of current therapies or expanding treatment regimens with more cytotoxic agents is likely to worsen toxicities with minimal improvement in survival rates.
Furthermore, a large portion (up to 30 kb) of the HSV genome is nonessential for the virus to replicate in cancer cells and, consequently, can be substituted with foreign DNA that can be used in several ways to enhance viral efficacy, such as by restoring the neurovirulence gene under control of a tumor-specific promoter to improve replication in tumor cells, by producing enzymes that disrupt and inhibit the tumor microenvironment, or by generating cytokines that can stimulate an immune response against the tumor. IL-12 is an example of a cytokine added to elicit an immune response via activation of natural killer and T cells.
RQT3-treated neuroblastoma and peripheral nerve sheath tumor xenografts not only showed delayed tumor growth but also had a reduced vascular density. Activated Ras or Ras pathway effector proteins, which are commonly found in human tumors, prevents protein kinase R activation, thereby permitting viral gene translation and resulting in an effective lytic infection. SVV has been used safely without dose-limiting toxicities in a phase I clinical trial in adults with advanced solid tumors (59).In preclinical studies, SVV has effectively killed cancer cells in a variety of pediatric solid tumors. Another promising approach to prevent infection in normal tissue involves deleting the B18R gene, which counteracts type I interferons.
Through genetic engineering, a wide variety of foreign genes may be expressed by oncolytic viruses to augment the oncolytic effect. The latest research has focused on determining which cells are responsible for tumor recurrence and finding ways in which these cells may be targeted in order to decrease toxicity and enhance quality of life and survival rates for children with cancer.Recently, the cells thought to be responsible for tumorigenesis, tumor maintenance, aggressiveness, and recurrence have been identified in a number of pediatric malignancies (2). The pediatric GBM D456MG was more sensitive to killing than several adult GBM xenografts tested (2,23).
Moreover, the treatment decreased circulating endothelial progenitors, indicating a possible antiangiogenic effect of the virus. Most adenoviral gene therapy vectors, including the most commonly used serotype 5 (Ad5), enter cells through the coxsackie adenovirus receptor (CAR), which is problematic because of highly variable (to absent) expression of CAR by tumor cells (35). Importantly, Ras activation has been shown to be an important mediator of tumorigenesis in various tumor types and may initiate tumor formation by expanding the stem cell population (53).


The B18R-deleted mutant results in interferon-mediated enhanced virus inactivation in normal cells (63).
We review the current data regarding the ability of several types of oncolytic viruses (herpes simplex virus-1, adenovirus, reovirus, Seneca Valley virus, vaccinia virus, Newcastle disease virus, myxoma virus, vesicular stomatitis virus) to target and kill both CSCs and tumor cells in pediatric tumors. After host-cell lysis and release of foreign products, cytokines can result in an immune response (T cells (T), natural killer cells (NK), and macrophages (MΦ)) against CSC antigens in uninfected cells.
Two mutant viruses, G207 and HSV1716, have been used safely without any dose-limiting toxicities in adult patients with recurrent glioblastoma multiforme (GBM) (Table 2 summarizes viruses included in the text) (18,19).
For example, neuroblastoma and medulloblastomas tend to express a higher degree of CAR than gliomas, which tend to have lower and variable expression (36).
Thus, the benign nature of the virus, its ability to target cancer cells with upregulated Ras signaling pathway, and the capability to deliver the virus systemically make it an appealing oncolytic virus.In preclinical studies, reovirus has been effective against pediatric malignancies. Like HSV and adenovirus, a large portion of the genome may be replaced with foreign DNA to augment oncolysis. We highlight advantages and limitations of each virus and potential ways in which next-generation engineered viruses may target resilient CSCs.
G207 is a doubly deleted, genetically engineered HSV that was originally derived from the wild-type clinical isolate, HSV-1 (F).
Moreover, normal epithelial cells, neurons, and astrocytes also express a high amount of CAR, which could result in adverse treatment effects. Importantly, CSCs are characteristically resistant to traditional chemotherapy and radiotherapy and, consequently, are believed to be responsible for tumor recurrence (6,7). Nestin is an intermediate filament protein that is expressed in embryonic neuroglial cells and has been used as a CSC marker in a number of cancers including brain tumors and neuroblastoma. Newer CRAds circumvent this limitation through modifications of the fiber knob of the viral capsid, thereby altering the tropism of the virus and enabling infection of cancer cells through a CAR-independent mechanism (34). VV that express antiangiogenesis proteins have been used successfully in preclinical studies to treat human adult solid tumors (65). Mechanisms that pediatric CSCs use to resist current therapies include efficient DNA repair ability with preferential activation of DNA damage response, upregulation of antiapoptotic genes, differential expression and phosphorylation of various kinases, increased expression of ATP-binding cassette (ABC) transporters, and relative quiescence (2).One of the main challenges for researchers is developing methods to identify and distinguish these cells from other tumor cells and normal cells in order to gain a better understanding of CSC biology and to develop novel targeted therapies to attack and kill CSCs. Insertion of the lacZ gene encoding β-galactosidase effectively disables expression of ribonucleotide reductase while providing a useful marker.
The virus not only infected and killed glioma CSCs but also inhibited their vascular niche in vitro (28). Not only was survival significantly increased in an in vivo mouse model, but spinal and leptomeningeal metastases, which are relatively common in MDB patients, were also decreased with intrathecal injections of the virus. Ewing’s sarcoma cells expressed CAR and were highly sensitive to viral oncolysis by adenovirus (37). Testing of SVV by the Pediatric Preclinical Testing Program confirmed a marked cytotoxic effect of the virus in some neuroblastoma cell lines (61). Preclinical studies in neonatal mice and New World owl monkeys (Aotus nancymae) that are as sensitive to wild-type HSV-1 as human neonates suggest that engineered HSV will be safe in pediatric patients as well (20,21). The virus prevented the CSCs from forming tumors in athymic nude mice, suggesting that the CSCs may be effectively targeted. OBP-301 (Telomelysin), a CRAd with a human telomerase reverse transcriptase promoter driving expression of E1A and E1B genes linked to an internal ribosome entry site, was cytotoxic in osteosarcoma cell lines that expressed CAR and suppressed tumor growth in a murine osteosarcoma xenograft model (38). In addition, RMS cell lines were highly sensitive to the virus, and there was an objective response seen in at least one rhabdoid tumor, Wilms tumor, and GBM cell line.
The efficacy of mutant HSV has been demonstrated preclinically in pediatric gliomas, medulloblastomas, and neuroblastomas (22,23,24,25). Compared with a control virus, Chase-ABCs spread throughout glioma spheroids more efficiently, and, through degradation of the extracellular matrix, the virus showed enhanced replication and antitumor activity in vivo. Telomerase plays an important role in tumorigenesis; telomerase activation results in cellular proliferation and can lead to mutagenesis and transformation, and telomerase appears to be overexpressed in CSCs compared with other tumor cells (39). Combining the virus with radiation or cisplatin enhanced the therapeutic effect.The only study examining the effects of reovirus on CSCs was in breast cancer. Although several Ewing’s sarcoma cell lines were sensitive to SVV in vitro, this effect was lost in vivo.
Most cells from five separate cell lines grown in serum-free medium as neurospheres, free-floating clumps of cells thought to be enriched for CSCs, were killed by the virus.
Oncolytic viruses use methods of cell killing that differ from traditional therapies and thus are able to elude the typical mechanisms that CSCs use to resist current chemotherapy and radiotherapy. It is important to note that the studies using VAE and Chase-ABCs were conducted in glioma cells from adult tumors, which in general are molecularly quite distinct from pediatric gliomas, and therefore the findings might not extrapolate to pediatric glioma CSCs.Although HSV is a neurotropic virus, it is capable of killing cells from a wide variety of nonneural cancers, including sarcomas, melanomas, colon, breast, lung, prostate, and hepatic tumors, and several adult human studies have demonstrated safety and antitumor effects (30,31,32).
Thus, therapeutics that target telomerase such as OBP-301 are promising agents to eradicate resistant CSCs.Although there are no specific studies examining the effect of CRAds on neuroblastoma CSCs, various adenoviruses have effectively targeted neuroblastoma cells, and two viruses have been used clinically in children with neuroblastoma (40,41,42). Breast CSCs, marked by CD24-CD44+ expression and overexpression of aldehyde dehydrogenase, were as sensitive to killing by reovirus as the non-CSCs (56).


The self-renewal ability of the cells grown in neurospheres was inhibited by JX-594 infection. Preclinical efficacy of G207 in pediatric rhabdomyosarcoma (RMS) and osteosarcoma cell lines was demonstrated by Bharatan et al. Notably, there were similar levels of Ras in the CSCs and the other tumor cells, suggesting that reovirus may effectively target chemotherapy- and radiotherapy-resistant CSCs. This study is limited by the lack of pediatric glioma cell lines and the lack of a specific CSC marker used to identify the CSCs.
This review will focus on the current research regarding the ability of oncolytic viruses to target and kill CSCs in pediatric tumors and highlight potential ways in which next-generation viruses may target resilient CSCs.
Further studies are needed to determine whether reovirus can effectively target CSCs from pediatric tumors.Multiple phase I and phase II studies of reovirus injected into the tumor bed or systemically have been or are currently being conducted in adult patients with central nervous system and extracranial solid tumors (9).
Not all cells within a neurosphere are undifferentiated CSCs, and, in fact, most may be differentiated tumor cells. Viruses that have already entered clinical trials or have been used clinically in children include herpes simplex virus-1 (HSV), adenovirus, reovirus, Seneca Valley virus (SVV), vaccinia virus (VV), and Newcastle disease virus (NDV).
We have found that the CSCs, marked by CD133, in both alveolar and embryonal RMS cell lines are equally sensitive compared with other tumor cells to killing with M002 (Friedman & Gillespie, unpublished results). The virus has a 24-base-pair deletion in the Rb binding site of E1A and the native E1A promoter is replaced with the cyclooxygenase-2 (COX-2) promoter. Nevertheless, the decrease in the number of neurospheres formed after infection with JX-594 suggests that the virus can target and kill some glioma CSCs. Viruses that are being studied preclinically for possible use in children include myxoma virus (MYXV) and vesicular stomatitis virus (VSV). The humanized IL-12 version of the M002 virus, M032, is being prepared for a phase I trial at the University of Alabama at Birmingham in adult patients with recurrent GBM. Cyclooxygenase-2 is believed to play an important role in tumorigenesis and cell survival by stimulating cell growth, invasiveness, and neovascularization, which are similar functions attributed to CSCs (43). Objective responses and disease stabilization have been reported with few side effects ranging from flu-like symptoms to mild gastrointestinal symptoms to neutropenia. In a panel of 10 primary human medulloblastoma xenografts, half of the tumors were sensitive to killing with SVV (58).
Using a Western Reserve strain of VV with mutations in TK and viral growth genes that is delivered to tumor cells by an ex vivo expanded natural killer T cell population (CIK-vvDD), Contag et al. Table 1 provides a comparison of the benefits and limitations of the viruses to be discussed below. No other studies to date have examined the effect of HSV on nonneural pediatric solid tumor CSCs. Injection of 1011 viral particles into the primary tumor bed resulted in a 71% regression of the primary tumor and clearance of metastatic bone marrow disease. Side effects included mild fever, diarrhea, stomach pains, and elevated liver enzymes that resolved in 2 wk. No specific CSC marker exists for murine lymphoma, and no human lymphomas were used in the experiments. Therefore, further studies are necessary to determine whether this dual biotherapy can indeed target and kill human CSCs. The virus was delivered intravenously by autologous mesenchymal stem cells, which may engraft in tumor stroma, and was well tolerated with the side effect of fever in three patients and an elevated liver alanine aminotransferase in one patient that resolved in 96 h.
Although three patients had no response, one patient had a very good partial response, suggesting that further investigation would be worthwhile.
Currently, there are no known ongoing studies of CRAds in children.Although not specific to pediatric brain CSCs, adenovirus vectors have shown promise in killing brain CSCs from adult glioma cell lines. The glioma CSCs expressed high levels of CAR and integrins and were targeted because of a defective Rb pathway not present in normal brain cells.
Delta-24-RGD is currently in a phase I trial in adults with recurrent malignant gliomas (NCT00805376). Survivin is a member of the inhibitor of apoptosis family of proteins that is overexpressed on adult gliomas but downregulated in normal tissue (46). In addition, the survivin promoter was radio-inducible with low-dose radiation increasing the cytotoxicity of CRAad-Survivin-pk7 in glioma cells. This effect was more pronounced in the CD133+ glioma cells, suggesting that the CSCs may have increased proliferative capacity following low-dose radiation. Thus, the potential benefit of CRAd-Survivin-pk7 to target pediatric CSCs is unclear.Skog et al.



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