Researches in cancer biology has discovered that carcinogenesis is a multi-step process which comprises mutations in oncogenes, tumour suppressor genes, genes involved in apoptosis and DNA repair mechanism. The mutations result in disruption of gene expression, cellular signalling and communication pathways. Consequently, malignant cells possess selective advantage of proliferation and growth over normal cells (Hanahan and Weinberg, 2000). A common principle behind multiple approaches to treating cancer is induction of cytotoxicity selectively in neoplastic cells. Conventional cancer therapeutics: surgery, radiotherapy and chemotherapy have achieved limited efficacy depending on the clinical stages and spread of tumours. In addition, there are the risk of drug resistance and toxicity of normal cells, thereby demanding for continued investigations and development of new strategies and agents to combat cancer.
Oncolytic virotherapy is one of the most extensively investigated approaches among diversity of new tumour treatment strategies. Since the early twentieth century, there have been case reports of cancer regression and temporary remission in patients with haematological malignancies who concurrently suffered from natural viral infection. Virotherapeutics has attracted clinicians and scientists to perform trials on advanced cancer patients using serum or body fluids harvested from patients infected with viruses. However, the interest in the research on virotherapy has been in fluctuation throughout twentieth century due to poor clinical response and unexpected toxicity. In 1948, ex vivo culture of human cells became possible which contributed to prove oncolytic potential of viruses in vivo by employing rodent cancer models. Subsequently, clinical trials in healthy volunteers and cancer patients, transplanted with subcutaneous tumour cell line, were conducted to validate the therapeutic potential of viruses against cancer. Suggestive anti-neoplastic effect was observed in clinical studies with Egypt 101 virus (Southam and Moore, 1952). The possibility of virulence in the patients treated with human pathogens had diverted the attention towards the use of non-human viruses like Newcastle Disease Virus and Vesicular Stomatitis Virus. With the progress achieved in the field of molecular biology and advances in recombinant DNA technology, various methods have been evaluated to construct safer and more efficient viruses (Kelly and Russell, 2007).
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Oncolytic viruses (OVs) are genetically engineered or attenuated to replicate preferentially in and destroy tumour cells through viral lytic cycle and induction of anti-tumoural immunity. Several viruses are currently under different stages of preclinical and clinical trials. The selective replication and lysis of viruses render therapeutic advantage of amplified concentration of input dose and spread within solid tumour. Because of these benefits, OVs display targeted effects against cancer cells with limited toxicity on normal cells (Chiocca, 2002). Oncolytic adenovirus H101 was the first achievement of virotherapeutic, approved by China FDA to treat HNSCC together with chemotherapy in November, 2005 (Garber, 2006). However, the clinical and systemic efficacy of oncolytic viruses is yet hurdled by several factors, necessitating further advances to overcome these obstacles.
Mechanism of viral oncolysis
A large variety of DNA and RNA viruses have been tested as potential anticancer agents. In general, viruses are manipulated to target the alterations in cellular signalling pathways that promote tumourigenesis: pathways of tumour suppressor proteins like p53, RB and RAS/ PKR pathways.
Inherently oncolytic viruses
RNA viruses such as Newcastle Disease Virus (NDV), Vesicular Stomatitis Virus (VSV) and Reovirus possess natural property of tumour tropism and oncolysis.
Newcastle Disease Virus
NDV is a negatively single-stranded RNA virus with natural avian host range and mild pathogenicity in humans. The application of NDV as an antineoplastic agent initiated from earlier studies with NDV natural infection in cancer patients. Experiments with 73-T strain of NDV in cultured cells proved its oncolytic potential (Cassel and Garrett, 1965). Lorence and colleagues suggested that NDV preferentially killed cancer cells by means of upregulation of TNF-α secretion and its activity (Lorence et. al., 1988). Local NDV therapy with 73-T strain demonstrated complete tumour regression in athymic redent model of human neuroblastoma (Lorence et. al., 1994).
The mechanism of variation in outcomes of NDV infection in normal cells and transformed cells has been proposed in a study carried out in 2006. After infection with NDV, IFN-β secretion was detected in normal cells in contrast to tumour cells. Rapid spread of the virus was noted in tumour cell line, which was correlated with poor IFN signalling pathways in malignant cells (Krishnamurthy et. al., 2006). The oncolytic ability of NDV could be accelerated with the manipulation of viral genome to express fusogenic F protein and various immunostimulatory molecules such as IL-2, TNF-α, and GM-CSF (Vigil et. al., 2007).
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Vesicular Stomatitis Virus
VSV is an enveloped virus with a single strand of genomic RNA, which occupies selective ability to infect and destroy tumour cells. The prerequisite for innate oncolytic capability is non-functional IFN system in cancer cells which support productive viral replication. The efficacy to attack malignant cells has been improved, through genetic recombination with immunomodulatory cytokines or suicide genes for activation of cytotoxic drugs. Two types of recombinants, VSV-IL-4 and VSV-TK, were constructed to express thymidine kinase enzyme for conversion of pro-drug ganciclovir to cytotoxic agent and IL-4 which assists in the development of effector immune cells and antibody immune response. Compared with non-engineered virus, they both exhibited greater tumour killing activity in vitro and in vivo models of melanoma, breast cancer and immune-competent model with lung metastases from mammary adenocarcinoma. Moreover, recombinant VSVs were capable of inducing anti-tumour immunity for eradication of present tumour and prevention of tumour recurrence (Fernandez et. al., 2002).
IFNs, secreted from helper T lymphocytes and natural killer cells, are necessary for protection against natural viral infection. Binding of IFNs to its specific tyrosine kinase-based receptor activates JAK-STAT signalling pathway, which in turn stimulates transcription of target genes including PKR, death ligand TRAIL and MHC antigens. Therefore, transformed cells, defected in IFN or PKR pathway, allow better viral replication, sparing normal cells. Engineered VSV with IFN-β gene elicited attenuated pathogenicity in normal cells whereas it maintained oncolytic efficiency in neoplastic cells with dysfunctional IFN pathway. Besides oncolysis, expression of IFN-β in surrounding normal cells controlled unwanted infection of normal cells (Obuchi et. al., 2003). Therefore, these studies have indicated the potentiality of VSV-based oncolytic viral therapeutics.
Reoviruses are non-enveloped icosahedral RNA virus with sub-clinical infection in humans. Duncan and colleagues reported that reovirus caused prolonged non-cytolytic infection in normal cells while it resulted in lysis of transformed cells (Duncan et. al., 1978). It was elaborated further that over-activation of Ras signalling pathway made transformed cells susceptible to reoviral infection through prevention of PKR phosphorylation of eIF-2α which normally inhibits viral gene translation (Strong et. al., 1998). Depending on the prevalence of Ras activation in malignant gliomas, oncolytic efficacy of reovirus was experimented in vitro, in vivo and ex vivo culture of patient derived brain tumours. The findings of significant responses: cell lysis, tumour regression and prolonged survival proposed reovirus as a potential oncolytic therapy for malignant gliomas (Wilcox et. al., 2001).
Genetically engineered oncolytic viruses
DNA viruses, adenoviruses, herpes viruses to give as examples, and some RNA viruses: influenza, measles are genetically manipulated to achieve specific replication and lysis in targeted tissues.
Adenoviruses are the most widely studied agent among oncolytic viruses both in preclinical and clinical trials, especially with serotype 2 and 5. It is a naked icosahedral dsDNA virus composed of five regions: E1A, E1B, E2, E3 and E4. Many factors contribute to the popularity of the virus as an oncolytic agent: firstly, it causes mild respiratory infection in humans. Secondly, its genome allows deletion of several regions for insertion of exogenous genes up to 10kb. Thirdly, there is little risk of random genetic recombination as viral genome stays in extra-chromosomal condition and the last but not the least benefit is being able to produce the virus in high titres with maximum amount of up to 1012 particles/ml (Aghi and Martuza, 2005).
Immediate early genes E1A and E1B are commonly targeted for mutation to restrict replication in tumour cells. In normal viral infection, these proteins are capable of forcing the infected cells to enter S phase for continuous viral replication by inhibiting RB and p53 respectively. In most neoplasms, RB and p53 pathways are mutated, which permit viral replication in contrast to normal cells. An example of E1B-55kDa deleted mutant is dl1520 (ONYX-015) while that of E1A-negative construct is delta24 (dl922-947) (Vaha-Koskela et. al., 2007).
The mechanism for tumour-selective replication of ONYX-015 was believed to be the lack of functional p53 in tumour cells which is normally inactivated by viral E1B protein (Bischoff et. al., 1996). That belief became questionable when it was noticed in some experiments that the viral replication was hindered in some tumours with p53 mutation, whereas the virus propagated well in cells with functional p53. The finding of the E1B-55kDa involvement in late viral mRNA export unravelled the alternate pathway for permissive viral replication in neoplastic cells. The translational levels of late viral proteins, which are essential for the viral coat assembly, exert an impact for the productive viral replication. It has been suggested that p53 concentration, together with transcriptional control function of p53 for proteins involved in apoptosis and cell cycle entry are determinants of tissue specific viral propagation (O'Shea et. al., 2004).
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Herpes viruses are enveloped, icosahedral and linear double-stranded DNA viruses with natural capability to evade host defensive barrier at several points and propensity to stay as latent infection in neuronal cells. There are many different strains of herpes viruses found as natural human infection, among them, HSV-1 and HSV-2 are chiefly investigated as an anti-cancer agent. From the study with thymidine kinase-deleted HSV in a mouse eye model, it was learnt that tk is necessary for effective viral replication in neurones (Coen et. al., 1989). One of late viral gene products, ICP 34.5, is responsible for neurovirulence, hence deletion of it is likely to minimize the risk of nervous system infection. Non-neurovirulent mutants have been designed by deletion of either one or both copies of ICP34.5 gene. One of them, known as R3616,HSV mutant with deletion in both copies of ICP 34.5, displayed reduction in the capacity to spread and replicate in nervous system in rodent models (Whitley et. al., 1993). Another mutated variant is G207 with removal of both ϒ34.5 and inactivation of ribonucleotide reductase enzyme, involved in viral DNA synthesis in quiescent cells. G207 demonstrated efficient targeted replication and lysis in transitional bladder cancer cell lines and murine models. Similar results were discovered in NV1020 strain, a chimeric mutant of HSV-1 and HSV-2 with mutation in tk gene, one copy of ϒ34.5 and the region between long and short segments of viral genome (Cozzi et. al., 2001).
Membrane fusion property of viruses is useful for rapid viral spread within tumour microenvironment as they bypass physical barrier with formation of syncytia. Fusogenic herpes viruses have been designed and their efficacy tested in many experiments. Oncsyn is recombinant HSV-1 with deletion of ICP-34.5 and mutation in viral glycoprotein B which induces cell fusion. Intratumoural therapy of the virus reduced the primary and metastatic growth in immunocompetent rodent model (Israyelyan et. al., 2008).
Influenza virus is a segmented negative-strand RNA virus whose genome encodes structural protein like nucleoprotein, viral polymerase, non-structural protein (NS1) and nuclear export protein (NEP). NS1 protein counteracts PKR-dependent antiviral reaction, thereby allowing viral replication in infected cells. Based on it, NS1-deficient influenza virus, delNS1, has been designed to preferential replication in tumour cells with defective PKR pathway. Activation in Ras-mediated pathway, found in nearly 30% of human cancers, inhibits PKR signalling by producing antagonists of PKR signals. DelNS1 grew markedly better in Ras-transfected melanoma cell lines than cell lines with wild-type Ras. Furthermore, the viral tumour-ablative potential was determined in SCID mice transplanted with N-Ras-positive cancer cells. Taken together, deficiency of NS1 helped the virus exclusively infect Ras overexpressed cancers by means of abrogating antiviral IFN-induced PKR response (Bergmann et. al., 2001).
It is an enveloped RNA virus with negative-stranded, non-segmented viral genome. Its cellular entry is mediated by binding of envelop glycoproteins: H and F, to cellular receptors, SLAM for both wild type and vaccine strain but CD46 is bound by vaccine strain only. Edmonston strain, MV-Edm, has been commonly used in the studies due to its less-pronounced infectivity. The oncolytic ability of MV was discovered from spontaneous remission of patients mainly with haematological malignancies after natural measles infection. To add up the inherent oncolytic function, it possesses membrane fusion property to enhance tumour spread and distribution.
Oncolytic viruses in clinical studies
Clinical testing has been carried out to address the issue of specificity and efficacy which cannot be fully translated from in vitro studies. Among loads of viruses, adenovirus, HSV, NDV and reovirus are commonly investigated in clinical trials. The evidence from these trials have suggested not only that oncolytic viruses are promising agents but also they work in synergy with standard anti-neoplastic therapies to fight against cancers. The first genetically engineered virus studied in patients is adenovirus (ONYX-015), whose efficacy has been examined widely in different tumour types.
It is the fourth most common cause of cancer death with a total five year survival rate of less than five percent from the time of diagnosis. It is aggressive tumour with potential of early local spread, resulting from a complex mutation in several genes including p53. Prognosis is poor in both resectable cases and advanced ones treated with combination therapies. In need of novel therapy, OVs are impending hope to get better prognosis.
Phase I study was performed in locally advanced cancer patients with the use of E1B-55kDa gene-deleted adenovirus, ONYX-015, exploiting the p53 mutation in most of pancreatic cancer. Different doses of the virus ranging from 108 to 1011pfu was administered intratumourally to determine MTD. Even with minimal result of tumour shrinkage, this study advised that adenovirus therapy was a feasible option with well-tolerated toxicity (Mulvihill et. al., 2001).
Clinical trial with intra-pancreatic injection of ONYX-015 via ultrasound-guided endoscope was conducted which results confirmed the low toxicity of virotherapy causing mild symptoms. No objective responses were observed after initial four sessions of single-agent ONYX-015 while partial regressions of more than fifty percent and 7.5 months medium survival time were achieved after combination with intravenous gemcitabine. This proposed that virotherapy in combination with chemotherapy enhanced the viral oncolytic efficacy (Hecht et. al., 2003).
Head and Neck cancer
SCC of head and neck region responds poorly to conventional therapy, and prone to recur after initial therapy. Because of the easy accessibility, locally advanced nature, and association with p53 mutation, local therapy with oncolytic virus, mainly adenovirus, was provided in clinical trials of recurrent HNSCC. Phase I trial investigated MTD (1011pfu/day) of ONYX-015 for intralesional injection (Ganly et. al., 2000).
To evaluate cytopathic effect and dosage schedule of adenovirus, phase II trials were carried out successively in 2000 (Nemunaitis et. al., 2000) and 2001 (Nemunaitis et. al., 2001). The virus was injected at a daily dose of 1x1010pfu for five days or same dose twice a day for 10 days over 3 weeks. Following that, the safety and response activity of ONYX-015 was analyzed in 2001, in which patients received a daily dose of 2x1011pfu for five days successively or two doses per day for two consecutive weeks. Results from these trials offered the therapeutic feasibility of oncolytic virotherapy in locoregional control of recurrent HNSCC, along with the hint to the neutralizing activity of antibody to virotherapy.
H101, E1B-55kDa gene-deleted adenovirus, similar to ONYX-015, was approved in China in 2005 based on the heartening results from phase III randomized trial in 2004. In this study, total 160 patients were treated with intra-tumour injection of H101 with doses varying from 5X1011 to 1.5X1012 VP/day for five consecutive days every three weeks. Concurrently, the patients were given cisplatin based therapy either ciplatin with 5-FU or cisplatin and adriamycin. The response rate of virotherapy combined with cisplatin and 5-FU (PF) was twice higher than PF alone, 78.8% and 39.6% respectively. Furthermore, only minor side effects, for example, fever, injection site reactions were observed (Xia et. al., 2004).
Systemic oncolytic virotherapy
Systemic administration of oncolytic virus to treat metastases and recurrent cancer has inspired by the satisfactory outcomes from trials with local injection. It has been ultimate aim of cancer therapeutics to stabilize and maintain progress in patients with systemic metastases.
Systemic efficacy of naturally attenuated strain of NDV, PV701, was examined in 79 patients with advanced solid cancers. Several dosages escalating from 12X109 pfu/m2 to 120X109 pfu/m2 were prescribed as a 10-minute injection or infusion based on four regimens. Patients were desensitized with one week cycle of an initial lower dose and two consecutive high-dose injections in every 28 days. The results showed that PV701 therapy was well-tolerated even at a dose ten times higher than a starting concentration, and common adverse effects were flu-like symptoms and transient hypotension. Safety outcomes in patients, together with low level of viral shedding in patients' body fluids sparked off the future application of viruses as systemic therapy (Pecora et. al., 2002). Another phase I study of PV701 was conducted by using two-step desensitization, with the hope of increasing tolerability of systemic viral therapy in advanced solid tumour patients. The results demonstrated less-pronounced toxicity and more-promising response: six-month of progress free period in four patients, compared with previous study (Laurie et. al., 2006).
In 2005, a group of researchers undertook phase I and II trial to test systemic efficacy and safety of NDV-HUJ in 14 patients with recurrent glioblastoma multiforme. Patients were infused with an starting doses of either 0.1, 0.32, 0.93, 5.9 or 11 BIU (Billion Infectious Unit) followed by three cycles of 55 BIU. No significant toxicities were observed while transient complete response for 3 months was seen in one patient (Freeman et. al., 2005).
Ovarian cancer is one of the most common gynaecological cancer, which is usually diagnosed at an advanced stage with peritoneal metastasis. Because of anatomic confinement of malignant lesions within abdominal cavity, intraperitoneal route was considered to be possible for systemic administration. Four dose cohorts: 109, 1010, 3X1010 and 1011 pfu of ONYX-015, diluted to a 500-ml volume, were injected via an intraperitoneal catheter. Follow-up studies assessed the toxicity profile, antibody titre, viral replication, besides, efficacy was determined by CA125 level and CT scan. Viral replication was studied in ascetic fluid, along with the potentiality of humoral immunity to limit viral replication. This study further highlighted that systemic virotherapy is a probable option with manageable toxicity (Vasey et. al., 2002).
Challenges in oncolytic viruses as cancer therapeutics
Although some achievements have been observed in the preclinical and clinical trials of oncolytic viruses, the effects are short-lived and tumour relapses after some period following virotherapy. Therefore, the hurdles and challenges have to be addressed for improvement of oncolytic viral therapeutics.
Challenges in oncolytic viral transduction and propagation
Successful viral infection is depended on the attachment and internalization of viruses to the cells. Cellular entry of majority of viruses is mediated by the interaction between viral proteins and cellular receptors.
Internalization of Adenovirus requires the binding between knob domain of fibre, which defined serotype specificity, and cellular receptors different for each knob domain (Louis et. al., 1994) (Stevenson et. al., 1995). After binding with CAR receptor on cell surface, the penton base interacts with cellular integrins αvβ3 and αvβ5 . The expression of CAR is heterogeneous among different cell types for example, bladder cancer cells (Li et. al., 1999). This finding correlated the differences in response of adenovirus therapy with various levels of CAR expression. Integration of a peptide with Arg-Gly-Asp (RGD) residue into HI loop of knob elicited CAR-independent viral entry (Dmitriev et. al., 1998). Taken together, modification of fibre protein is reasonable to expand tissue tropism regardless of CAR status in tumour cells.
Challenges in oncolytic viral efficacy
In most preclinical and clinical studies, little success has been made to determine MTD of viral therapy, meaning that administration of large amount of viral load is needed to achieve therapeutic response. Saying that, it has raised the concern regarding with safety and complication of virotherapy in cancer patients, who are more or less immunocompromised. On top of that, tumours regressed partially even with large viral dosage in single local treatment with oncolytic viruses (Parato et. al., 2005). Similarly, limited response has been detected in systemic administration in treatment of metastases. Intravenous therapy with high dose of recombinant VSV was briefly effective in metastatic breast cancer model (Ebert et. al., 2005).
Challenges by immune system
The effects of immune response on virotherapy is controversial, neither advantageous or disadvantageous. Following cellular entry, viruses produce proteins and transcription factors to replicate within the cells. Consequently, viral factors attract host innate immune cells, which processed and presented viral antigens to cytotoxic T lymphocytes (CTL). CTLs destroy viral infected cells, preventing successful viral replication, thereby reducing therapeutic efficacy.
On contrary, immune attack targeting virally infected cancer cells could be beneficial to patients. Release of anti-viral cytokines might contribute to the local tumour clearance (Davis and Fang, 2005).
Challenges by tumour microenvironment
Tumour microenvironment is critical for restriction of viral replication and promotion of tumour growth. Tumour hypoxia alters viral replication, that was evidenced in the study with adenoviruses in which viral replication was restricted in hypoxic regions (Shen et. al., 2006). Tumour vasculature and extracellular matrix also play as an impediment of viral therapy. Fibrosis and necrosis in tumour hinder efficient viral spread so that targeting tumour microenvironment might improve the viral oncolytic efficacy.
Strategies to improve oncolytic viruses as cancer therapeutics
Recently researchers have investigated and developed several strategies to conquer the limitations and challenges of antineoplastic viral therapy.
To enhance systemic viral delivery
Major determinant for effective viral delivery is neutralizing antibodies and complement factors in circulation which kill the viruses soon after they administer. To evade immune response, different types of carrier cells, namely endothelial cells, mesenchymal stem cells and T lymphocytes, are tested and shown to bring better systemic efficacy (Liu and Kirn, 2008). Adenoviruses were cleared rapidly from systemic circulation, predominantly by receptor-mediated viral uptake by hepatocytes and scavenger function of Kupffer cells, which makes the viruses less accessible to peripheral targets. Coating of viruses with multivalent polymer extended systemic half-life of the virus. Polymer-coated adenovirus were injected intravenously into immunocompetent rodent model, in which upregulation of viral bioavailability and downregulation of hepatic toxicity were identified. Polymer based viral delivery appears to be a plausible platform to augment systemic viral therapy (Green et. al., 2004).
To enhance tumour specificity
Targeted infection and replication of viruses in tumour cells could be succeeded through insertion of tumour specific promoter or modification of surface receptor.
Insertion of tumour specific promoter
There are two types of TSPs, either pan-cancer specific for targeting a variety of tumours or tumour-type specific promoters. An example of first category includes telomerase promoter as telomerase overexpression characterizes one of the hallmarks of cancer, limitless replication. Studies has been done to assess the feasibility of hTERT integration to upstream promoter sequence of early viral genes, required for viral replication. High expression of Cox-2 is discovered in epithelial tumours involving ovarian adenocarcinoma. Cox-2 promoter carrying recombinant adenovirus replicated and killed Cox-2 positive cancer cells while causing minimal lysis of non-malignant mesothelial cells (Kanerva et. al., 2004). In the same way, sequence encoding peptide proteins like AFP for hepatocellular carcinoma, PSA in prostate cancer and CEA for colorectal carcinoma are inserted as tumour-type specific promoters (Fillat et. al., 2010).
Modification of surface receptor
As mentioned above, viral entry to the cells required cellular receptors, CAR in case of adenovirus and CD46 or SLAM for measles viruses to name a few. Natural tissue tropism of viruses could be expanded by modification of cellular receptor. Measles virus glycoprotein H was modified to express scFv anti-CD20, which would bind to CD20 found on surface of both normal and neoplastic B cells. MVHαCD20, CD20 targeted MV, did not infect and enter CHO cells unless transfected with CD20 as CHO cells were non-permissive for MV. On top of that, there was multinucleated syncytia formation between tumour cells after infection with high titres of virus. Thus, scFvCD20 incorporated MV offered two benefits: extension of viral tropism to CD20 positive cells and rapid viral spread by formation of syncitia from membrane fusion (Bucheit et. al., 2003).
To enhance viral efficacy
Attempts to enhance the anti-cancer efficacy of viruses have been constantly explored and developed.
Combination with conventional therapy
Sub-optimal responses studied in preclinical and clinical trials have suggested the combined regimens for cancer treatment. Heterogeneous phenotype of cancer reflects mulit-targeted approach. In order to optimize the cytotoxic capacity of virotherapy, they are given in mixture with standards treatment modalities: chemotherapy and radiotherapy. Both viral therapy and other therapies sensitizes each other to benefit the patients of completer cure. VEGF inhibitors enhanced localization and spreading of circulating viruses in immunocompetent redent model when given together. Tumour regression was promoted due to direct cytolysis as well as viral-mediated immune attack on tumour vasculature (Kottke et. al., 2010).
Complementing with therapeutic genes
Customized oncolytic viruses with therapeutic genes: immunomodulatory genes, anti-angiogenic factors complement the oncolytic function of the viruses. OncoVEXGM-CSF is developed from HSV-1 strain with deletion in one copy of ICP34.5 and ICP47 and harbouring GM-CSF which has been studied to replicate selectively in targeted cells with minimal toxicity. The intratumoural injection of the virus elicited necrosis and high level of immune cells infiltration in tumour biopsies, indicating that the virus is capable to destroy cancer cells and expression of GM-CSF enhances anti-tumour immune response, acting synergistically (Hu et. al., 2006).
Targeting cancer stem cells
Cancer stem cells (CSCs) consist of a subpopulation of cancer cells, which play a critical role in tumour initiation, development of metastasis. They are one of the reasons for failure of various therapeutic approaches. Markers of CSCs has recently been discovered in a range of cancers, particularly CD133 is associated with glioblastoma, liver, colon, prostate and pancreatic cancer while CD44 is related with melanoma and breast cancer. Attempts to target CSCs with oncolytic viruses, adenovirus and herpes viruses, have been investigated, paying attention not to harm normal stem cells as they share similar features (Short and Curiel, 2009).
Numerous oncolytic viruses are in the pipeline to enter clinical trials, meanwhile new constructs of recombinant viruses have been developed with the use of several tactics for better efficacy and lesser undesirable side effects. Advances in preclinical models will validate preclinical data to be translatable to clinical outcomes. With fine-tuning of the viral specificity and efficacy without neglecting microenvironment, oncolytic viruses are promising options of cancer therapeutics.