ABSTRACT: The term cancer deters every individual due to its high mortality rates.Inspite of recent advances in the felid of medicine the deaths occurring due tocancer remains unchecked.
The conventional methods of treatment have lowtherapeutic effects and high risk of side effects. Further the possibility ofre-occurrence is not completely eliminated by any of the conventional methodsof treatment. Thus, a technique that affects only the tumour cells withoutleaving behind any cancer initiator cells must be deviced. Recently genetically modified variants of measlesvirus were used to cure multiple myeloma .The idea to use of measles virusdates back to 1950’s.Constant research has lead the advent of a branch known asoncolytic virotheraphy . Specifictargeting of cancer cells is obviously one of the major advantages of oncolyticvirotherapy and it can be achieved in several ways.
Some viruses such asautonomously replicating parvoviruses, reovirus, Newcastle Disease Virus, Mumpsvirus, Moloney leukemia virus have a natural preference for cancer cells,whereas such as measles, adenovirus, Vesicular Stomatitis Virus, vaccinia andHerpes Simplex Virus can be adapted or engineered to make them cancer-specific. INTRODUCTION:For more than a hundred years,viruses have been pursued as able experimental agents to eliminate or regress neoplastic growths. Understandingviruses accelerated in the 1950s and 1960s, immensely due to the advent of celland tissue culture systems which allowed exvivo virus propagation.19,20 An early approach for the cure of cancer wasthrough a toxin commonly known as the Colley’s toxin. The toxin containedkilled bacteria and proteins. Though Colley’stoxin was not proven to be beneficial (8)1,later scientist tried to useinfections for the of cure cancer. In 1950’s it was noticed that West Nilevirus had tumour shrinking properties.
West Nile virus had the risk of causingor developing a disease which is known as West Nile encephalitis. Thereforeclinical trials had to come to an end (8). The history of oncolyticvirotheraphy dates back to the 12th century that documentedspontaneous regression of haematological cancers after wild measles infection.During the past fifty years,viruses have been studied with such unparalleled intensity that their biologyis now understood more thoroughly than that of any other organism in nature.
These untitring efforts have led tobetter understanding of their genomesand proteins,their physical structures, their replication cycles andpathogenetic strategies futher the ability to regulate their genomes have been deviced . (history)After constant research, Oncolytic viruses were engineered. Varioustypes of viruses like herpes virus, influenza virus, pox virus are being testedfor their oncolytic properties (11).The oldest vaccine used for the eradicationof small pox is being researched for its oncolytic properties(7). The modern era of oncolytic virotherapy, in whichvirus genomes are engineered to enhance their anti-tumor specificity, can betraced to a 1991 publication in which a thymidine kinase (TK)-negative herpessimplex virus (HSV) with attenuated neurovirulence was shown to be active in amurine (7, 5).Presently the mostcumbersome task is to find out the right kind of virus for destruction ofparticular type of tumour cells. Recently the cure of multiple myeloma wasbrought about by injecting genetically modified variants of measles virus.
Thisnews brought the field of oncolytic virotheraphy into lime light.Though a surgical cure to cancerswas often reported, the likelihood of success depended greatly upon a tumorbeing quickly diagnosed and somewhat readily accessible. ( history ) ONCOLYTICVIROTHERAPHY: Viruses are natrue’s gift that specifically infect and lyse the tumourcells (10).The use of one of the categories of oncolytic virus belonging to oneof the below mentioned groups forms the basis for oncolysis.
1. Wildstrains that affect the cancer cells2. Attenuatedmutants of human virus strains3. Virusesattenuated by culturing techniques Ingeneral the viral genes act as tumour destructive agents and the capsids actsas vehicles (10). As mentioned previously, a particular virus to destroy tumourcells of a particular origin or function, hence a right virus for the cancerhas to be found. Oncolytic viruses derive their speficity by either explotingthe cell surface receptors or intracellular gene aberrations which are overexpressed in cancer cells (10). One of the greatest advantages of oncolyticvirotheraphy is the ability to engineer the virus according to the outcomes ofclinical trials.
Cancer cells show altered cell physiology like insensitivityto inhibitory growth signals, extensive replicative potential, tissue invasionand metastatis and sustained angiogenisis. These alterations in cell physiologymake selective replication of the virus possible (13). These cancer targetingmechanisms of viruses can be broadly achieved by two general approaches either by deletion of viralgenes required for virus replication in normal cells or by the use oftissue/tumour specific promoters for critical viral genes (12, 4).Experiments performed with other oncolytic viruses, such as herpes virus andreovirus, have demonstrated that cyclophosphamide can decrease the innateimmune response, prolong viral gene expression and proliferation in tumours,and enhance oncolytic viral effect(2).Alternate mechanisms to target cancer cells are also devised. One of them is to selectively eliminate the undesirable tropism by specifically engineering thevirus for various specified target organs into their genomes so as tofacilitate the selective blocking of the virus’s life cycle in the target organs like brain,liver , muscle specific micro RNA.
Another method is to alter the viruses so as to produce immune –stimulating chemicals. An alternative way to ‘target’ viruses tocancer cells is to selectively eliminate their undesirable tropisms byengineering targets for brain-, liver- or muscle-specific microRNAs into theirgenomes so that the viral life cycle is selectively blocked in the relevanttarget tissue(6).At-times, oncolytic viruses are genetically modified toproduce immune-stimulating chemicals or to make them more specific for cancercells(8) CURE FOR MULTIPLEMYELOMA: A clinicaltrial at the Mayo Clinic suggests that a modified version of themeasles virus can be used to target cancer cells and put thecondition into remission.
Researchers intravenously delivered 10,000 times thetypical dosage of measles vaccine to two women, 49- and 65-years-old, who hadmultiple myeloma, a rare cancer affecting white blood cells in bone marrow. Thevirus, which was modified to specifically target cancer cells, reduced oreliminated tumours in the two patients. . In addition to the multiple myeloma trial, themodified measles virus is being tested in glioblastoma multiforme(brain cancer) and ovarian cancer (6).
The measles virus was genetically modified to contain mammalian NISgene. On injecting the modified variants of the virus, the tumour cells arebestowed with the capacity to concentrate radioactive iodine i.e. the genecontains information that enables the of iodine from the blood stream to thetumour cells (6, 3). The presence ofradioactive iodine within the tumour cells enables easy tracing of themalignant cells with the help of iodine markers (7).After injecting measles,the patients suffered from short livedsymptoms like fever, low blood pressure and also rapid heart attack( 4).
Theover expression of CD46 by the malignant plasma cells(myeloma cells) makes it atarget of choice for the measles virus .In short the life cycle of measlesvirus complements that of myeloma cells. Genetically modified virus gains access to the bone marrow by infectingthe RES.
The viruses seek and destroy the tumour by multiplying within thetumour cells. In addition, the oncolytic effect of the MV-NIS straincan be synergistically augmented by administering the ? and ? emitter .131IMVstrains have been successfully retargeted to display a variety of ligands suchas single-chain antibodies against epidermal growth factor receptor, epidermalgrowth factor receptor vIII, CD38, 28 folate receptor ?, 30 Her-2/neu, 31 CD20,24 and cytokines such as interleukin, targeting receptors overexpressed intumour cells (7).
One of the important challenges in the development ofMVstrains as cancer therapeutics involves preclinical toxicology testing giventhe significant limitations of existing animal models as rodents do not expressthe MV receptors CD46 and SLAM. Toxicology studies of ivy administration of the MV-NIS virus wasperformed in cynomolgus monkeys. MECHANISM OFONCOLYSIS:Measles virus is anegative strand RNA paramyxovirus. It contains 6 genes that encode 8 proteins,the proteins being 1. Nucleocapsid(N)2. Phospho(P)3. Matrix(M)4. Fusion(F)5.
Haemagglutinin(H)6. Largeproteins (L) and small proteins (C andV) (7) Theviruses enter the cell by pH independent membrane fusion. The receptor andmembrane fusion takes place which is mediated by H and F proteins respectively.
Interaction between two receptor present in the cancer cells namely CD46 andsignalling lymphocyte activation system (SLAS) and the H protein takes place.The expression of CD46 helps the tumour cells to escape apoptosis as the cellsprotect themselves from complement activated lysis. After the process ofreceptor recognition by the H protein conformational changes of F proteinleading to fission and viral entry (7, 10). Therefore typical cytophaticeffects of measles virus are dueto the formation of gaint mononuclear cellaggregates. The formation of syncytia can significantlyenhance the antitumor effect of the virus because, for each infected cell, 50–100neighbouring cells may fuse and form sancta, followed by apoptotic cell death 16 .The derivates ofmeasles virus are tumour specific and has minimal cytophatic effects onnon-transformed and normal cells(11). Measles virus infection is said to cause profoundimmunosuppression, thereby making the measles patients susceptible to secondary infections which inturnaccounts accounts for high morbidity and mortality2. TheEdmonston strain of measles virus, and vaccine strains derived from it, use asa cellular receptor human CD46 (refs 3, 4), which isexpressed on all nucleated cells; however, most clinical isolates of measlesvirus cannot use CD46 as a receptor5.
Here we showthat human SLAM (signalling lymphocyte-activation molecule; also known asCDw150), a recently discovered membrane glycoprotein expressed on some T and Bcells 6, is acellular receptor for measles virus (including the Edmonston strain).Transfection with a human SLAM complementary DNA enables non-susceptible celllines to bind measles virus and supports measles virus replication and developcytopathic effects. The distribution of SLAM on various cell lines isconsistent with their susceptibility to clinical isolates of measles virus. Theidentification of SLAM as a receptor for measles virus opens the way to a betterunderstanding of the pathogenesis of measles virus infection, especially theimmunosuppression induced by measles virus.(10) Progressin the domain of virotheraphy hasbeen achevied by keeping in mind various stratergies like· Suppression of innate immuneresponse enhances efficacy· Carrier cell strategy avoidsimmune attack· Targeting tumormicroenvironment enhances viral spread and efficacy · Oncolytic viruses kill cancerstem cells· Genetic engineering ofoncolytic viruses complements · chemo-and molecular-targetedtherapies· Genetic engineering ofoncolytic viruses targets cancer signaling pathways · Novel oncolytic virus speciesare being explored ,· A large number of clinicaltrials have to carried out Suppressionof innate immune response enhances efficacy: The interaction between virus-immune system have been extensively studied in the contextof virotherapy.
Innate immune responses to the virus are a major hurdle for long-termgene expression and oncolytic potency. The use of immunomodulatory agents incombination with oncolytic viruses was first reported in the 1970s. Variousstudies have demonstrated the efficacyof cyclophosphamide to inhibitneutralizing antibody induction, macrophages, regulatory T cells induction and intratumoral interferon(IFN)-gproduction. Though suppression of immune system enhances the efficacy the treatment and thereby influencing theoverall prognosis to a great extent, it is yet to be determined,if thisapproach would be beneficial in patients with varying degrees of pre-existing immunosuppression either due to disease and chemotherapy.
Carrier cell strategy avoids immuneattack: A novel approach of increasing the favourable outcome of this remedy is by blocking the host immune response .By blocking the immune responses one can take advantage of theimmune system to boost antitumor responses. Cytokine-induced killer (CIK) cellsare known to ones’ own immune system and destroy tumor cells . After isolatingthe CIK cells from mice, these cells were infected with oncolytic vaccinesviruses and re –administered intotumor-bearing animals. As a result, substantially larger amounts of oncolyticviruses were delivered to the tumor.
Therefore it was noted that both the CIK cells and oncolytic viruses were synergistic in tumorkilling. A drawback of thisapproach is that this approach is that it requires harvestingof cells from individual patients, ex vivo culturing and redelivery to thepatients and thereby requiring asubstantial amount of laboratory work. Nonetheless, this strategy holds promisein expanding the potency of the approach .
Targeting the tumor microenvironmentenhances viralspread and efficacy: tumormicroenvironment plays an important role inrestricting viral spread and promotingtumor growth several approaches havebeen taken.The first is to engineer viral vectorswith therapeutic. Coadministration of matrixmodifyingagents (bacterial collagenase, MMP-1, 8)has been shown to enhance the spread of oncolytic HSV,24,25 although concernsabout tumor metastases have to beexplored in more preclinical modelsbefore translation into clinical trials.transgenes that target the keycomponents of the tumor microenvironment . Tumor hypoxia and its impact onviral replication have also been studied. Another important issue is to explore how inflammation induced by virusinfection impacts on the tumormicroenvironment. Pretreatment withcyclophosphamide suppressed the inflammation and resulted in reduced tumorvascular permeability.30 Kirn et al.
31showed that systemically administered vaccinia virus resulted in infection andsubsequent destruction of tumor endothelial cells, which led to loss of tumorvascular density. The efficacy ofvirotherapy can be limiting when replication-mediated oncolysis is the sole MOA Oncolytic viruses kill cancer stemcells: from the recent discoveries inthe filed of cancer stem cells, it has become clear that the neoplastic cell populations not only initiatetumorigenesis, but also contribute primarily to resistance to chemo-and radiation therapy. As these cell populations are capable of replication and self renewal,oncolytic viruses that are designed to target cell cycle-dysregulated tumorcells might also possess theability to kill cancer stem cells.The mechanism of action would include replication-induced celllysis in other words necrosis andautophagy that is degradation ofintracellular components inlysosomes Genetic engineering of oncolytic virusescomplementschemo- and molecular-targetedtherapies: Genetic engeneering of the viruses allows functionalcomplementation to chemotherapeutic agents and molecular-targeted therapeutics. Novel oncolytic virus species are beingexplored: As most oncolytic viruses have shown to produce less than optimal efficacy inclinical trials as single agents, there is great interest in exploring novelviral species. These studies assess oncolytic activity and/or investigate tumorselectivity.A large number of clinical trials havebeen carried out: Virotherapy has several features that are distinct from othertherapeutics.
Its multiple novel MOAs include replication-mediated oncolysis,antitumoral immunity induction, antiangiogenesis, apoptosis and autophage induction.There is no cross resistance with other therapeutics, and synergisticinteraction is seen with other treatment modalities. Safety in human has been demonstratedin more than 800 patients. In addition, current biotechnology allows us torapidly address issues encountered in clinics at the bench. CONCLUSION: Although a range of therapeutic options for battling neoplasms including surgery, chemotherapy, and localablative therapies are available , the prognosis for major neoplasms remains poor with a median years or months of survival .Despite significant progress in recent years, most advancedmalignancies remain incurable and hencethere is an immediate need for thedevelopment of novel therapeutics wasdetected.
antitumoral effect has been achieved .3, 5–9 inspite of exploration of various therapeutic alternates , namely hormonal therapy, immunotherapy, and gene therapythe complete cure for the neoplasmsremains a true challenge .10–12 The currentapproach for the treatment of malignancies is gene therapy , to use viral and nonviralgene therapy systems. gene-based therapeutics has considerable promise as atreat modality . Though gene therapy was initially conceived as a strategy fortreating monogenic diseases, its scope has eventually broadened to include the in vivo expressionof foreign gene products that can cause tumor cell lysis. Theefficacy of new generation oncolytic virus is one of the key issues. Increasein anti –tumour activity is being brought about either by incorporating susidegenes in the genome or by transiently suppressing the immunity for viralinfections. These methods apart from increasing the efficacy also increase thetoxicity (15).
Higher risks of viral replication are present with immunesuppression. This modality of treatment needs a lot of research as there are noproven ways to monitor the in-vivo spread, elimination and for the measurementof viral gene expression and kinetics (8). Cyclophosphamide, a novelstrategy is currently being developed to circumvent antimeasles immunity andfacilitate systemic delivery in future applications of this technology (11).One such concept includes the use of cell carriers such as monocytoid celllines or mesenchymal stem cells, which could protect MV from the immune system,transfer the virus, and efficiently deliver it to tumour cells (13).
Intracvenously administered viruses are rapidlycleared from the circulation as a result of sequestration by the mononuclearphagocyte system in the liver and spleen. Before clearance, they are opsonisedwith antibodies, complements, coagulation factors and other serum proteins thatfacilitate their recognition by splenic macrophages and hepatic Kupffer cells.These particles bind to receptors like Fc? receptors, complement receptor 1(CR1), CR3 or scavenger receptors on macrophages and endothelial cells,resulting in receptor-mediated phagocytosis and accelerated clearance from thecirculation(7,14).Strategies to minimize sequestration include chemicalmodification of the coat proteins of the viruses by conjugation ofbiocompatible polymers, such as polyethylene glycol.
These developments in themethod of treatment help to improve the prognosis of the patient and also helpsto reduce the mortality and morbidity rate due to cancer (14). The increasingincidence, the lack of effective therapies, and the devastating prognosis ofHCC support the urgent need for new therapeutic agents that are both safe andeffective.(15) .