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Signs herpes outbreak is coming

Figures released by the World Health Organisation (WHO) last week stated that 417 million people in the age group 15-49 age group are living with HSV-2. There are two strains of herpes simplex virus, the first strain of HSV-1 is commonly referred to as cold sores or mouth sores; the second strain of herpes HSV-2 causes painful genital sores and the only available treatment is daily doses of antiviral drugs that can reduce but not eliminate outbreaks. The WHO estimates of infection rates have been shocking for many as it is far larger than first thought and makes the need to deliver a therapeutic vaccine that can not only prevent HSV-2, but also treat people who may already be infected all the more important.
Admedus is working with Australian of the Year, Professor Ian Frazer, to harness his next-generation DNA vaccine technology in an effort to create a therapeutic vaccine for HSV-2. Admedus’ HSV-2 therapeutic vaccine is designed to enable, boost and support the body to fight against the disease. The Admedus HSV-2 program has already completed a successful Phase I study, with results showing no safety issues and with 19 of 20 of the study participants showing a T-cell response where no previous immunity existed which is an early indicator of an effective immune response. The HSV-2 therapeutic vaccine is now in a Phase II study and the primary endpoint of the study is the safety of the vaccine in people with the virus, and Admedus will be looking at additional endpoints such as reduction of symptoms and viral flares, which are related to HSV-2 lesion outbreaks, after vaccination.
Admedus has had hundreds of people register to participate in the Phase II study, and we are nearing full enrolment. The clinical study design has an initial screening, after which study participants have a 45 day baseline observation period on trial entry before receiving the first of their three therapeutic vaccine injections. Luckily for you folks, OKC Atheists LURVES to do parades, so they put a handy guide of tips up on the OKC Atheists blog! Also known as a cold sore, this lesion is caused by the contagious herpes simplex virus Type-1 (HSV-1), and should not be confused with a canker sore, which is not contagious. The recent estimates highlight not only the significance of this virus, but also the need to find a cure. If the name Ian Frazer sounds familiar, it’s probably because his originating work lead to the marketed vaccine Gardasil, which is used to prevent HPV infections and the associated cervical cancers in 120 countries protecting millions of young people. Therapeutic vaccines are aiming to treat disease rather a preventative vaccine, meaning it can be used in people who already have the disease, not just as a preventative measure, which is traditionally how vaccines are used. More than 80% of the required study participants have either received their initial dosing regimen and the program is on track to have interim data by the end of 2015, with additional data from the study being available in 2016.
The trial is exploring two injection regimens, which will be administered by intradermal injection three times, with a four week break between each injection regime. Lahiri* Amity Institute of Biotechnology, Amity University, Noida, India Email address: (S. The different therapeutic strategies like radiotherapy, chemotherapy and surgery, used individually or in different combinations, do not remove tumors or their progression all the time.
In case of surgery, which is possible only before metastasis, even a single cancer cell left out during surgery, cause further cancer. Focus has been laid in developing agents that could specifically target the cancer cells and leave out the remaining normal cells.
Over the last two decades, due to various advancements in molecular biology, virotherapy has seen various developments. A special class of viruses called oncolytic viruses have been used as a therapeutic strategy against cancer. These agents have various inherent and engineered factors like enhanced tissue tropism, thereby providing high selectivity; armed with transgenes to deliver therapeutic genes and to perform tumor selective replication, all these factors proving them improved and evolved mechanisms, when compared with other cancer therapeutics. The purpose of this paper is to provide a detailed account of some of the current observations, developments and insights made in the field of oncolytic virotherapy for targeting colorectal cancer cells.
The colon is continuous with the small intestine proximally at the ileocecal valve and ends distally at the anal verge.
The rectum, 10cm in length in the adult, begins at the peritoneal reflexion and follows the curve of the sacrum ending at the anal canal. Colonic Crypt Organization The colon is organized into four histologically distinct layers.
The epithelial layer, at the luminal surface, consists of a single sheet of columnar epithelial cells folded into finger-like invaginations that are supported by the lamina propria to form the functional unit of the intestine, called crypts of Lieberkühn (Lc). The terminally differentiated cells (enterocytes, goblet cells, and endocrine cells), which are found in the top third of the crypt, are derived from multipotent stem cells located at the bottom of the crypt. During asymmetric division, these multipotent cells undergo self-renewal and generate a population of transit amplifying cells that, upon migration upward through the crypt, proliferate and differentiate into one of the epithelial cell types of the intestinal wall. The fourth type of cells, the Paneth cells, differentiates during a downward migration to the base of the crypt, where they reside below the stem cell population1. These functions include modulation of the intestinal microflora and maintenance of mucosal defense barriers A normal human crypt contains roughly 2,000 cells and approx. Several molecules have been proposed as markers of stem cells in the intestine, including Musashi-1 (Msi-1), Hes1, integrins I±2 and I?1 subunits, EphB receptors, Bmi-1, Lgr5, and Aldh12, 3.
This represents the crypt of Lieberkühn, (a) Normal intestinal epithelium (b) Tumorigenic intestinal epithelium. Epidemiology Colorectal cancer (CRC) is the third most common cancer in men (746,000 cases) and the second in women (614,000 cases) worldwide. The malignant potential of adenomas increases with size, grade of dysplasia, and degree of villous components, along with the number and order of genetic and epigenetic aberrations. Growth and Expansion Although research was on since 1970s, Michael Bishop5and Harold E Varmus (1985)6first reported the concept of Cellular Oncogene meaning that the responsible oncogenes are already present in every cell. Under conditions of activation of them by any of the physical, chemical or biological agent (mostly viruses), it cause uncontrolled growth, the genesis of cancer. The earliest histologically recognizable lesion in colorectal cancer formation is the aberrant crypt focus (ACF)7.
The cells in these aberrant crypt foci may appear normal, forming hyperplastic tissue, or the cells may have abnormal intracellular and intercellular organization, forming dysplastic tissue. The likelihood that hyperplastic polyps will become cancer is very low and are quite often found to be asymptomatic. These polyps are not malignant themselves, but have a chance of becoming cancerous if not removed.
Sometimes the carcinoma is confined to the polyp, and other times it invades one or more layers of the intestine. The risk of an adenoma developing into cancer increases as the size of the adenoma increases and with the extent of time they have been growing in the colon. Transition to Cancer When a normal cell undergoes stress or damage, the tumor suppressor protein p53 suppresses cell division or induces apoptosis in response to it.
Cancerous growth usually require release from the protective control of p53, over cellular birth and death. Allelic losses on 17p occur in less than 10 percent of early or intermediate stage adenomas, increasing to about 30 percent in late adenomas and rising to about 75 percent in cancers. Migration of the cancerous cells and condition greatly alters the environment in which they live. Molecular Origin The genetic events include increases in cellular proliferation and the silencing of genes involved in inhibition of proliferation and apoptosis. The accumulation of mutations involving oncogenes and tumor suppressor genes follows the progression of the disease along the adenomaa€“carcinoma sequence, in which the neoplastic process, initiated by APC or I?-catenin mutations and tumor progression, results from the sequential mutation of other genes, such as K-Ras and p53, in the context of a growing genomic instability. The different types and subtypes of cancer in a particular organ are determined by the different 'cells of origin'. These cells acquire the first genetic hit or hits that culminate in the initiation of cancer10.
Rare tumor-initiating cells with stem cell-like properties in both hematopoietic and solid malignancies have been identified and classified using distinct cell surface markers. These cancer stem cells (CSCs) can self-renew and differentiate to generate the cellular heterogeneity of the originating tumor11. Cancer Therapy: Then and Now Until the early twentieth century, surgery was the most practiced form of treatment for cancer therapy. However for those with late diagnosis or inaccessible tumor, survival was rarely reported12. This therapy was the first to bring about regular remissions, chemical compounds for the treatment of cancer became more practiced than radiation compounds or surgical methods.


Although hematological malignancies appeared susceptible to many chemotherapeutics, solid tumors were barely affected.
As with its predecessor technologies, by the 1950s, reasonable doubts were raised against chemotherapy if it alone would prove a panacea as a cancer treatment14. Both these practices have their respective side effects like vomiting, diarrhoea, fatigue, hair loss, sexual and reproductive issues etc., owing to their aggressive mechanism of action.
Combination therapy of acceptable oncolytic viruses with herbal remedies should be attempted as the guideline for the prevention and cure of cancer.
History of Oncolytic Viruses In 1923, it was reported for the first time that tumors are more susceptible to certain viruses, acting as a sponge attracting viral replication than normal cells16. Later in 1950s at National Institute of Health (NIH) it was found that adenovirus was able to target and kill HeLa cells in a culture.
Oncolytic virotherapy was then included as a part of treatment strategies for cancer and in a study involving cervical cancer patients, it was observed that many tumors had regressed17, 18. Surface protein modifications were done on the capsid to achieve tumor targeting, enhance infectivity and potency 19.
Virotherapeutics which are therapeutic oncolytic viruses are a class of anticancer agents that are targeted to have improved and evolved mechanisms of action when compared with other cancer therapeutics like radiation and chemotherapeutics. Compared to the crude methods practiced in the 1950s, now virotherapeutics use in vitro-passaged strains (first generation), to genetically engineered selectivity-enhanced viruses (second generation) and finally to genetically engineered transgene-expressing 'armed' oncolytic viruses (third generation)20.
Even though most of the viotherapeutics are still in initial stages of the trials, some have cleared the phase III and are commercially available in particular countries such as Gendicine and Oncorine approved by China for head and neck cancer 21.
The purpose of this review is to provide a detailed account of this field of research and bring forth some of the current observations, insights and ideas circulating in the literature. We have strived to cover  as many different oncolytic viruses as possible to give a broader picture of targeting colorectal cancer cells using these viruses. Selection Criteria for Virotherapy Due to widely differing structures, lifecycles mechanisms and cellular tropisms of different viruses, resulting in highly distinctive clinical manifestations, specific oncolytic viruses would be ideally suited to a specific malignancy. Most of the oncolytic viruses currently in development show a relatively broad spectrum of antitumor activity, such as oncolytic adenoviruses were initially considered for therapy of epithelial malignancies but now are also studied against hematologic cancers; similarly HSV and measles virus are considered for other malignancies apart from what they were originally found for.
However due to safety issues, broad spectrum antitumor activity is preferred in clinical studies, and in a downside study, it was found that they get attenuated when they reach their target.
Thus all the assumptions regarding safety and host range need to be tested experimentally in appropriate animal species. Some of the factors carefully monitored are virus tropisms, mutability, anti-apoptotic and cytotoxic gene products, anti-viral immunity and drug availability to remove any unwanted products23.
The safety considerations that need to be checked while using an oncolytic virus include cancer specificity, regaining pathogenecity, transmissibility, undesired side effects and pre-existing immunity.
In order to overcome most of the risks included, non-human viruses are preferred for oncotherapy. This includes mechanisms such as serotype switching and polymer coating even if the immune system is invoked, the antibody cannot distinguish the virus particle and use of cellular vehicles24, 25. Till date four different markers, Carcinoembryonic antigen (CEA), MUC1, Guanylyl cyclase C 26, 27, 28, KRAS 29, 30 and Tp5331, have been studied extensively with wide applications which have been explained later.
Adenoviruses The human adenoviruses (Ads) belong to the Mastadenovirus genus in the family Adenovirus which are unusually stable to chemical or physical agents and adverse pH conditions, allowing for prolonged survival outside of the body. The icosahedral structure of the adenovirus has a capsid of 252 capsomers covering 36kbp linear dsDNA. Even though as monotherapies, oncolytic human adenoviruses have shown limited clinical efficacy, they are envisioned as novel, replication-based treatments for human malignancies. Various principles have been employed such as Directed Evolution to generate highly potent Ads with specific altered properties such as efficiency of cell lysis, infectivity, and viral DNA replication or by arming therapeutic viruses with therapeutic transgenes34. Recently however, there are several late stage clinical trials showing promise which may eventually lead to clinical acceptance35.
Mode of Action For most of the serotypes Ad infection is initiated by the fiber knob domain binding to a cell surface receptor CAR (coxsackie-Ad receptor) which causes the penton base to interact with the integrins. The viral genome is released into the nucleus of the cell resulting in selective expression of viral proteins in early phase and genome replication followed by expression of late genes in late phase. The late phase is followed by assembly and maturation of the virus triggering cytolysis and release of viral progeny. The delayed and late genes encode viral structural proteins and the proteins necessary for virus assembly. This new generation Ad vector elicits a much reduced in vivo immune response in animal models and prolongs transgene expression, while maintaining relatively high transduction efficiency and wide tropism. Induce apoptosis, block proliferation and metastasis of tumor cells Head and neck, lung, melanoma, prostate, breast, thyroid, ovary, colon, bladder, gliomas, etc.
B7) Enhance systematic immune function, immunogenicity of tumor cells and anti-tumor immunity Solid tumors (e.g. IL-2, TNF, etc.) Readjust the host immune system to be more sensitive to a specific, but often weakly immunogenic tumor-associated antigen, for cancer treatment and prevention Cervix, prostate, breast, melanoma, colon, etc. Ads simultaneously expressing both antisense ornithine decarboxylase and adenosylmethionine decarboxylase inhibit colorectal cancer cell growth in vitro. Recombinant poxviral vectors expressing CEA and its various co-stimulatory molecules have been explored since the 1990s with very uninspiring results. During tissue receptor binding, the capsid fibre binds to CAR receptor of tissue inducing the penton base to recruits I±I? integrins via an RGD (Arg-Gly-Asp) motif resulting in internalization of the virion via receptor-mediated endocytosis. However since it is exposed on the outer surface it could be genetically altered to target cell surface receptors.
Oncolytic, Conditionally Replicative Ads (CRAds) The selectivity of CRAds is crucial for its tumor-specific targeting which are achieved either during infection or during replication. For example, the CRAd prototype ONYX-015 is able to replicate only in p53 deficient tumor cells. Adenoviral Strains Currently Under Clinical Studies ONYX-015 In current clinical application, ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. During a phase II trial of a combination of intra-tumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck, a high proportion of complete responses observed for 6 months, where none of the responding tumors had progressed, with acceptable toxic effects38, 39.
This virus has several changes relative to the parent Ad11p virus to enhance the tumor selectivity and host cell lysis 40. Anti-VEGF antibody expression by these tumors could be detected in the tissue as both mRNA and functional antibody42. Herpes Simplex Virus The herpesvirus family consists of a group of viruses distinguished by the large size of their linear double-stranded DNA genomes (∼130a€“250 kbp) and a common architecture of infectious particles. Based on their biological properties such as growth characteristics and tissue tropism, herpesviruses can be further divided into three subfamilies. Among the eight human herpesviruses, the alpha subfamily includes neurotropic viruses and contains the herpes simplex virus (HSV) 1 and 2, and Varicella zoster virus (VZV)43.
HSV DNA consists of two unique sequences: Unique Long (UL) and Unique Short (US), which are separated by terminal inverted repeats. ICP6 is essential for viral DNA replication and gene g34.5 is the major neuropathogenicity gene in HSV. Multi-gene deletions confer great selectivity and safety on HSV; however, deletions of mutations lead to a reduction in neurovirulence and clearness of the virus by host immune response. Mode of Action An organ culture system was developed from colon carcinoma and healthy colon tissues of mouse and human origin and was infected with HSV-1at a very low efficiency, in contrast to high-efficiency infection of colon carcinoma tissue. It was found that two extracellular components, collagen and mucin molecules, were found to restrict HSV-1 infectivity in the healthy colon. The mucin layer of the healthy colon binds to HSV-1 and thereby blocks viral interaction with the epithelial cells of the tissue.
In contrast, colon carcinomas express small amounts of collagen and mucin molecules and are thus permissive to HSV-1 infection. For example, NV1042 delivers immuno-modulatory molecule is IL-12 which can invoke CTLs, helper T lymphocytes and NK cells has shown significant anti tumor effects on murine model of micro-metastatic liver disease.


Similarly, OncovecGM-CSG expresses a Granulocyte macrophage colony-stimulating factor (GMCSF) gene which activates T cells to exert a cytotoxic effect on the tumor cells. Also, the a47 promoter increases the expression of MCH-I, thereby improving the tumor antigen presentation. Clinical studies with patients having colorectal adenocarcinomas metastatic to the liver showed major reduction in tumor size when administered intravenously in conjugation with chemotherapy46. Reovirus Reovirus belongs to the Reoviridae family, which includes viruses of a variety of tropisms (with examples of animal-, plant-, and insect-pathogenic viruses) and, most notably, the major human pathogen, rotavirus.
Unlike the clinically significant rotavirus, reovirus is relatively nonpathogenic in humans.
There are three serotypes of reovirus, based on their hemagglutination-inhibition activity, found ubiquitously in environment. Prototypical laboratory strains of each serotype were isolated from childrena€™s respiratory and enteric tracts and are designated Type 1 Lang, Type 2 Jones, Type 3 Abney, and Type 3 Dearing47. The genome consists of linear double stranded RNA 18kb-30kb long packed within each virion. Mode of Action When a viral surface protein binds to the extracellular domain of EGFR, it stimulates a tyrosine kinase activity of the receptor which in turn auto-phosphorylates EGFRa€™s cytoplasmic tail.
Phosphotyrosine binding adapter molecules, such as Grb2, are recruited to the tail which recruits the protein Sos to the plasma membrane, where it stimulates the exchange of GTP for GDP on the small G protein, Ras. Ras signals may sensitize cells to reovirus by blocking cellular defences against viral infection. Viral protein synthesis is thus blocked, the replication cycle is halted, and the cell survives. In cells with activated Ras pathway signaling, however, PKR phosphorylation and activity are impaired and viral translation ensues. The lytic cycle can then proceed: secondary transcription and translation occur, and final particle assembly ultimately precedes death of the transformed cell. Cells in which PKR expression is knocked out behave just as Ras-transformed cells, substantiating the necessity of PKR in the antiviral response of normal cells. Reoviral Strain Currently Under Clinical Study Reolysin It is a wild type strain of Type 3 Dearing reovirus developed by Oncolytics Biotech. Reoviral infection in normal cells causes activation of cellular PKR (dsRNA-activated protein kinase) and aborting of viral protein translation and replication.
In tumor cells, PKR was found to stay inactivated and unable to arrest viral translation, replication, and cytolysis. This mechanism increases the succeptibility of  Ras pathway by utilizing the over expression of upstream elements of Ras gene such as EGFR or PDGFR48. It was also found to show selective replication in KRas transformed human epithelial cells in cell lines study. Reolysin could be used in conjugation with tunicamycin or brefeldin whose proteasome inhibitor causes enhanced ER stress-mediated apoptosis49. Reovirus has been evaluated in murine and humans via the intratumoral and intravenous route resulting in tumor regression with mild toxicities and consisted of transient flu-like symptoms and headache.
It doesna€™t cause insertional mutagenesis in a host cell despite of being a DNA virus as its entire life cycle occurs in the cytoplasm in rapid replication cycles. Inactivation of TK gene of vaccinia results on its increased dependence on cellular concentration of TK for replication which is over-expressed in cancer cells. The JX-594 strain has been developed to be active against EGFR inhibitor-resistant tumors both in vitro and in patients.
This is of significance as TICs are known to be generally resistant to currently approved chemotherapies52.
This oncolytic virus class is therefore growing rapidly, and elucidating the selectivity mechanisms that these agents exploit will be critical to maximize patient benefit and the design of future products in this class.
Newcastle Disease Virus Newcastle disease virus (NDV) is an avian virus of the family Paramyxoviridae and genus Avulavirus, with a 15kb long single stranded negative sense RNA genome, causes a highly pathogenic disease recognized originally in 1926 at England and as of date causes a deadly infection in both domestic and wild spanning over 250 species of birds, with a range of symptoms, causing major losses to the poultry industry all over the world. Depending on the virulence and severity of disease caused, NDV strains can be divided into three different pathotypes: velogenic (high virulent), mesogenic (mild virulence) and lentogenic (low virulence) strains. Molecular Composition The virus famil Paramyxoviridae consists of helical capsid symetry. The viral genome, 10-20kb long, codes for 6 gene products: nucleocapsid protein, nucleocapsid associated protein, matrix or membrane protein, fusion protein (Fo uncleaved and F1,2 cleaved), haemagglutinin-neuraminidase and large polymerase protein. These viral particles generally appear to have a 100-500nm diameter and are covered with spike like projections with glycoprotein composition usually 8-12nm long which aid in host cell adhesion53. This induces a conformational change on F protein releasing the fusion peptides, fusing viral and cellular membranes. Immunostimulatory Property of NDV Irrespective of the oncolytic effect, NDV has immunostimulatory properties some of which are summarized in the following table. On delivery of NDV, peripheral blood mononuclear cells (PBMC) cytotoxicity was significantly enhanced with NK cells predominantly causing lysis.
Anti Cancer Properties of NDV Owing to its superior rate of replication in a human neoplastically transformed tumor cell than a normal cell and its oncolytic effects, NDV has gained interest in the scientific population around the world.
First reports of its application date back to 1950s when NDV and adenovirus were used to treat uterine carcinoma resulting in partial necrosis. However this was soon followed by re-growth, probably due to production of neutralizing antibodies against the virus.
Many studies were followed exploiting these viral agents with the available technology proving a huge possibility of overcoming different cancers with the oncolytic effects of these viruses.
Mode of Action NDV mediated cytotoxicity occurs by 2 mechanisms: firstly, by interaction of HN viral protein with tumor cell surface evoking an immune response and secondly, by local induction of cytokines. 54 Depending on the mode of oncolysis, NDVs have been evaluated and classified as lytic or non lytic strains. The lytic strains cause syncytia formation to induce changes in the plasma membrane resulting in lysis of target cells.
Non lytic strains cause tumor regression slowly by disrupting normal host cell metabolism, preventing further tumor growth without causing lysis. Tumor Selectivity Initially the selectivity of NDV was proposed to be due to defective IFN type 1 response in tumor cells permitting NDV replication. However, effective oncolytic activity in cancer cell lines possessing a robust IFN response proved that another factor may be responsible for this selectivity.
However, if this form of defence mechanism occurs prior to viral assembly, it could prevent further viral infection thereby lowering the net oncolytic effect. In a study using A549a€“Bcl-xL cells it was found that NDV- mediated cytolysis and fusogenicity are enhanced compared to those in A549-neo cells. Presence of significantly higher viral titers and viral proteins in A549-Bcl-xL cells than in A549-neo cells indicated that viral replication was enhanced in apoptosis resistant cells. A549a€“Bcl-xL cells showed an over-expression of Bcl-xL, allowing early NDV replication and production of type 1 IFN thereby inducing activation of apoptosis by antiviral signaling.
This subsequently led to higher number of cells being infected during the following viral replication cycles allowing deeper tumor penetration and oncolysis with low initial viral inoculums. After initial virus entry, non-cancerous cells quickly undergo apoptosis, resulting in non-productive infection, while apoptosis-resistant cancer cells survive longer, producing more virus particles and initiating new rounds of infection. This was proven in a study wherein melanoma showing chemoresistance to IAP Livin was found to undergo oncolysis on administration of NDV-HUJ. Conclusion and Future Prospects Colorectal cancer is one of the major health concerns in the world being the third most frequently diagnosed cancer in men and women.
Conventional chemotherapy or radiotherapy has limited effects against many forms of cancer, not to mention a plethora of treatment-related side effects signifying a need for novel therapeutic strategies, and one such approach is the use of viruses19. Oncolytic viruses are viruses that are able to replicate specifically in and destroy tumor cells, by the virtue of an inherent or engineered property.



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