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Oncoviruses: An overview of oncogenic and oncolytic

Article in Oncobiology and Targets · January 2015 DOI: 10.4103/2395-4469.163581

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Monal Yuwanati Shubhangi Mhaske People's College of Dental Sciences & Research Centre, Bhopal, Peoples University

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Access this article online : An overview of oncogenic Quick Response Code: and oncolytic viruses

Shubhangi Mhaske, Monal Yuwanati, Nikita Bhatnagar

Abstract: Website: www.oncotargets.com The knowledge of tumor biology has created the potential to develop and understand the mystery of the oncogenic and oncolytic viruses. The facts with viral oncogenesis have surprised the mankind by the development of DOI: oncolytic therapy by the viruses themselves. The objective of this paper was to overview the concept of 10.4103/2395-4469.163581 oncogenesis and oncolysis by the deoxyribonucleic acid and ribonucleic acid viruses. In spite of the fact that viruses indulge in causing , advances are also being made in the field of oncolysis by viral therapy. Although in its infancy, oncolytic viral therapy has already produced some notable successes. The viruses are selectively modified with incorporation and deletion of genes required for them to be tumor‑specific. These modified oncolytic viruses are also used in oncolysis of oral cancers by administrating them either intratumorally or systemically. With diverse nature of tumors, some being radio‑resistant and another chemo‑resistant, the notion of oncolytic viruses being used as adjunct to the conventional treatment modalities is of great significant value. This paper presents an overview of the various aspects of oncogenic and oncolytic viruses in a concise manner with discussion about the mode of administration of oncolytic viruses, their scope and their future potential in treatment of oral cancers. Key words: Adenovirus, Epstein‑Barr , herpesvirus, oncogenic virus, , oral , tumor suppressor genes

Introduction are governed by complex regulatory networks and are surveyed by mechanisms that certify that Oncogenic viruses abnormal cells are removed from the proliferative The concept of cancer etiology seems to be pool. OV inactivate these surveillance incomplete without mentioning the indispensible mechanisms that would normally recognize role of viruses. There were 10.9 million new cases, and put out such abnormal cells. Viruses are 6.7 million deaths, and 24.6 million persons alive accepted as causative factor for human cancer. with cancer (within 3 years of diagnosis).[1] As Different guidelines had been proposed to aid estimated, 15% of all human cancers worldwide in establishing a causal relationship between may be attributed to viruses, expressing a viruses and cancers [Table 3]. Although few of significant cancer burden worldwide.[2] Much the guidelines are not applicable for all viruses, of what is known today about cancer and its still they are quite useful. related genes responsible for cancer causation Department of can be attributed to the studies on oncogenic Mechanism for Viral Oncogenesis Oral deoxyribonucleic acid (DNA) and ribonucleic [3] and Microbiology, acid (RNA) viruses. Epstein‑Barr virus (EBV), The characteristic feature of is loss [4] Peoples Dental Human Papillomavirus (HPV), hepatitis B of growth control by escaping the checkpoint [5] [6] Academy, Bhopal, virus, and human herpesvirus‑8 are the during normal cell cycle. The retinoblastoma (Rb Madhya Pradesh, India documented DNA viruses contributing to gene) and p53 genes are main tumor suppressor the . Human T lymphotropic genes involved in checkpoints. Rb gene acts as virus type I (HTLV type I)[7] and hepatitis C an ON‑OFF switch for the cell cycle. This gene Address for viruses (HCV)[8] are the RNA viruses that are brings about its action by forming tight inactive correspondence: considered to be oncogenic viruses (OV).[9] The OV complex with the transcriptional factor (E2F) Dr. Monal Yuwanati, are enlisted in Table 1 with their tumor‑specific which is thus not available for progression of Department of Oral Pathology, Peoples types. The various milestones in the discovery of cell cycle. The main role of p53 in a normal cell Dental Academy, Peoples various OV have been enlisted in Table 2. cycle is of surveillance and triggering check point Campus, Bhanpur, controls that slow down or stops the cell cycle. It Bhopal - 462 037, Viruses being obligatory intracellular parasites mediated its action by transcriptional activation Madhya Pradesh, India. encode proteins that reprogram host cellular of p21 (member of Cip/Kip family along with E-mail: monal9817@ signaling pathways. This in turn controls p27 and p57) at the G1/S checkpoint of the gmail.com the proliferation and differentiation of cells, normal cell cycle. Alteration in these normal Submission: 26‑03‑2015 cell death, integrity of the genome and also pathways by OV (which act as initiators) may Accepted: 17‑05‑2015 recognition by . These processes lead to uncontrolled proliferation of the tumor

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cells. This transformation of the normal cells into cancer cells Table 2: Important milestones in history of OV usually occurs with two distinct phases of Initiation and Year Discoveries/contributions/key events Promotion. The tumor suppressor genes encode proteins that 1903 Advanced the hypothesis of the infectious nature of restrain cell growth and are part of the negative control of cell cancers cycle regulation. The mutation in these genes primarily leads to 1907 Discovery of HPV the uncontrolled proliferation of the cells. The Rb gene encodes 1908 Identification and discovery of avian virus a 928‑amino acid phosphoprotein, Rb which is phosphorylated 1911 Discovery of avian RSV [11] by cyclin‑dependent kinase. This phosphorylation leads to 1933 CRPV discovered the release of binded E2F and permits the G1 to S transition 1935 Induction of in domestic rabbits by and thus the replication occurs. In case of p53 gene, there is CRPV‑first DNA tumor virus expression of protein (p21) that inhibits the cdc2 kinase. This 1936 Mouse mammary tumor virus‑discovered a milk basically prevents the premature entry of the cell into the S factor, which they considered to be responsible for phase of cell cycle. However, if the cell lacks the functional p53 the mammary adenocarcinoma of the mouse protein due to damage of wild type of p53 gene, there may be 1947 A virus identified as the causing agent of Rous [12] progress toward the transformation of the cell. The mutated 1951 Murine leukemia virus discovered genes are now referred to as those codes for a protein 1953 Mouse polyomavirus discovered that can potentially transform normal cell into malignant cell 1953-54 Human adenovirus discovered if these oncogenes are transmitted by viruses they are called as viral oncogenes. 1961 SV40 discovered by Eddy at NIH, and Hillman and Sweet at Merck laboratory as a rhesus macaque virus contaminating cells used to make of Salk and Various viruses mainly responsible for the development of Sabin polio oral cancers with their mechanisms of tumorigenesis have 1964 The initial discovery of herpes‑type viral been described. These mechanisms vary for both DNA and particles (EBV) later on linked to specific human RNA viruses. malignant disease was made 1966 Was awarded the Noble Prize for his pioneering Deoxyribonucleic Acid Oncogenic Viruses work in animal tumor viruses 1967-68 HBV discovered Human papillomavirus 1970 Reverse transcriptase discovered In case of Papillomaviruses, there are two oncogenes E6 1974-84 Link found between HPV infection and cervical and E7. These are associated with HPV types 16 and 18 cancer and are able to mutate large set of cellular genes. In case of 1975 Link between HBV infection and HCC Papillomaviruses, the two oncogenes, E6 and E7 genes of 1976 Cellular origin of retroviral oncogenes discovered HPV types 16 and 18, modify a large set of cellular genes. 1976 HBV developed – first cancer vaccine These oncogenes either functionally inactivate the cellular 1979 P53 tumor suppressor discovered genes or target them for degradation. They either change 1980 T‑lymphotropic retrovirus type I was discovered in 1981 1980 and linked to adult T‑cell leukemia Table 1: Virus‑associated tumors 1981 A firm link of HBV to became apparent Viruses Tumor types from epidemiological studies was published EBV Burkitt’s 1983 Starting in 1983 and 1984 novel types of anogenital 1984 papillomaviruses were isolated directly from cervical under cancer immunosuppression 1986 E2F discovered Hodgkin’s disease 1988-89 Interaction of Rb tumor suppressor with DNA tumor Subset of T‑cell lymphomas virus oncoprotein demonstrated HBV HCC 1989 HCV and its link to HCC discovered HPV Anogenital cancers, oral 1991-92 Development of HPV/ HPV 16, 18, 31, 33 and others cancers (20%) 1994 KSHV and its link to Kaposi’s sarcoma HPV 5, 8, 14, 17, 20 and others Cancers in patients with 1996- Association of several polyomavirus with human HPV 20, 23, 38 and others epidermodysplasia verruciformis 2008 cancers of 2008 Chang and Moore, now at the University of the skin Pittsburgh Cancer Institute, developed a new Human herpesvirus type 8 Kaposi’s sarcoma method to identify cancer viruses based on Body cavity lymphoma computer subtraction of human sequences from a HCV HCC tumor transcriptome, called DTS RSV Rous sarcoma 2008 Discovering and lining of MPV with MCC HTLV type 1 Flaviviridae Adult T‑cell leukemia 2010- Development of therapeutic cancer vaccine 2014 HCV HCC OV=Oncogenic viruses, HPV=Human papillomaviruses, RSV=Rous sarcoma MPV MCC? virus, CRPV=Cottontail rabbit papillomaviruses, SV40=Simian vacuolating HCC=, EBV=Epstein‑Barr virus, HBV=Hepatitis B virus 40, EBV=Epstein‑Barr virus, HBV=Hepatitis B virus, HCC=Hepatocellular virus, HPV=Human papillomaviruses, HCV=Hepatitis C virus, RSV=Rous carcinoma, HCV=Hepatitis C virus, KSHV=Kaposis sarcoma virus, sarcoma virus, MPV=Merkel cell polyomavirus, MCC=Merkel cell carcinoma, DTS=Digital transcriptome subtraction, MPV=Merkel cell polyomavirus, HTLV type 1=Human T‑lymphotropic virus type I MCC= Merkel cell carcinoma, DNA=Deoxyribonucleic acid

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Table 3: Guidelines proposed by various authors Modified from zur Hausen The regular presence and persistence of the respective viral DNA in tumor biopsies and cell lines derived from the same tumor type The demonstration of growth‑promoting activity of specific viral genes or of virus‑modified host cell genes in tissue culture systems or in suitable animal systems The demonstration that the malignant phenotype depends on the continuous expression of viral oncogenes or on the modification of host cell genes containing viral sequences Epidemiological evidence that the respective virus infection represents a major risk factor for cancer development Evans and Mueller guidelines Epidemiologic guidelines Geographic distribution of viral infection corresponds with that of the tumor, adjusting for the presence of known co‑factors Viral markers are higher in case subjects than in matched control subjects Viral markers precede tumor development, with a higher incidence of tumors in persons with markers than those without Tumor incidence is decreased by viral infection prevention Virologic guidelines Virus can transform cells in vitro Viral genome is present in tumor cells, but not in normal cells Virus induces the tumor in an experimental animal Hill criteria for causality[10] Strength of association (how often is the virus associated with the tumor?) Consistency (has the association been observed repeatedly?) Specificity of association (is the virus uniquely associated with the tumor?) Temporal relationship (does virus infection precede tumorigenesis?) Biologic gradient (is there a dose response with viral load?) Biologic plausibility (is it biologically plausible that the virus could cause the tumor?) Coherence (does the association make sense with what is known about the tumor?) Experimental evidence (is there supporting laboratory data?) DNA=Deoxyribonucleic acid

their expression pattern, by functionally inactivating them or proto‑oncogenes. In addition to this, HBV encodes for various by targeting them for degradation. Both E6 and E7 co‑operate proteins like HBV X protein, S viral proteins, Pre S2 activators to induce transformation of epithelial cells. A fully malignant and hepatitis B spliced proteins. These proteins are thought phenotype is observed only after prolonged cultivation of the to affect the apoptosis of the infected cells, causes immune transformed cells with chromosomal instability induced by modulation, cause genetic instability and induce cell cycle action of E6 and E7 protein of HPV. This supports the multistep proliferation.[14] nature of HPV‑induced transformation.[13] Association of E6 with p53 leads to degradation of p53 via recruitment of an Hepatitis C virus ubiquitin ligase, E6‑AP, and results in the inhibition of the Hepatitis C virus is an enveloped RNA virus with genome transcriptional regulatory activities of the p53 protein in tissue of 9.6 kb that encodes for a single polyprotein. It is one of the culture cells.[12] major causes of liver disease including cirrhosis and HCC. The oncogenic mechanism is not clear as for HCV but may virus be associated with integration or affected through chronic (HSV) is a natural pathogen to infection, or direct, virus‑specific mechanisms may be involved. humans, and infection can cause lethal encephalitis. It is an There is translation of genomic RNA into a viral polyprotein. enveloped virus, approximately 200 nm in diameter, with a This viral protein is cleaved into the capsid protein (C), the two double‑stranded DNA (dsDNA) genome of approximately glycoproteins E1 and E2, a small protein (p7), viral proteases 153 kbp encoding approximately 90 genes. NS2 and NS3, and nonstructural proteins NS4A and 4B and NS5A and 5B, which are required for viral RNA replication.[15,16] Hepatitis B virus This leads to formation of HCV viral proteins which causes Hepatitis B virus (HBV) is a major causative factor in the interference with cellular proteins, which are responsible for development of hepatocellular carcinoma (HCC). About the regulation of cell cycle control. Two possible mechanism 15–40% of infected individuals will develop chronic active explained in HCV oncogenesis are (i) by suppression of the hepatitis that can in turn lead to cirrhosis, liver failure, or cell cycle regulatory gene p21 in response to its interaction HCC. Like retroviruses, the replication of HBV is dependent to p53 and (ii) the loss of host‑cell genomic stability due to on reverse transcription. But, unlike them, integration of HBV deregulation of Rb pathway. The interference of cellular genome into the host cell genome is not necessary for their proteins and HCV core protein is considered a major risk factor replication, although it might aid the process of development for the progression of HCC. of carcinoma with chronic inflammation, especially in the cases of liver cirrhosis. The integration results in the transpositions Epstein‑Barr virus and deletions of the viral sequences from one chromosome to Epstein‑Barr virus is a ubiquitous dsDNA virus. It belongs to other. This results in genomic instability and activation of the the γ herpesvirus subfamily of the lymphocryptovirus genus.

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Its association with lymphomas has been of great interest. polyomavirus to be clearly identified as a carcinogenic agent EBV is responsible for encoding of a variety of proteins. for human cancer, and MCPyV was recently classified as The major proteins are the EBV latent membrane proteins a 2A .[18] The capsid protein VP1 interacts with 1 and 2 (LMP 1 and LMP2). LMP 1 is thought to interact N‑acetylneuraminic acid of gangliosides that are important for with tumor necrosis factor receptor‑associated factors. This viral entry and integration of the plasmid into the host cell.[19] in turn leads to the increased activity of NF‑kB, Jun, P38 in The MCV large T ([LT] ) modulates helicase activity, LMP‑1 expressing epithelial cells and B cells. This interaction which plays a key role in viral replication by binding the origin of leads to the induction of Bcl‑2 family members and thus replication and triggering. There are many plausible mechanisms the induction of anti‑apoptotic genes. While LMP‑2 causes by which the MCV induces cell transformation. The most activation of PI3K/AKT survival pathway. EBV also encodes knowable path involves constitutive expression of LT and small for EBV nuclear antigen 2 and 3 (EBNA 2, EBNA 3). EBNA‑2 T (sT) proteins, with the hypothesis that MCV LT is the primary proteins along with EBNA‑LP acts as transcriptional activator oncoprotein and sT exerts an accessory role in carcinogenesis.[20] of both cellular and viral genes leading to their excessive proliferation.[14] Oncolytic viruses In the earlier centuries, it had been observed that cancer patients Ribonucleic acid oncogenic viruses who contracted an infectious disease went into brief periods of The RNA viruses associated with human cancer mainly clinical remission. Viruses have been pursued as experimental belongs to Retroviridae and Flaviviridae families. Duesberg agents of cancer destruction for more than 100 years. Interest and Vogt[17] compared the genomes of two closely related in the field has seen fluctuations during this time, gaining replication‑competent Rous sarcoma virus (RSV) variants, in its height in the 1950s and 1960s. This was followed by which one variant could transform cells and the other could not. near‑abandonment in the 1970s and 1980s and a revival of The results demonstrated that the transformation‑competent interest in the past two decades. This culminated in the first RSV variant at the level of the 3‑end exhibited additional marketing approval of an oncolytic virus, granted by Chinese sequences. This accounted for a genome 20% larger than the regulators for the genetically modified oncolytic adenovirus one of transformation‑defective RSV variant. This H101 in November 2005.[21] There are two types of viruses that was later named src according to the type of tumor caused by have been studied. One of the types is having natural preference RSV in chickens, the sarcoma. This leads to the establishment for the tumor cells, and the other type includes that virus that of the hypothesis that the reverse transcriptase dependent has been genetically modified for their use in oncolysis. Some life cycle of most RNA OV like RSV allows the viral genome of the viruses with their tumors for which they are used have to capture cellular oncogene. After a short interval since the been mentioned in Table 4. time of infection, the RNA genome is reverse transcribed by the virally encoded reverse transcriptase into dsDNA copy. Mechanism of viral oncolysis This copy then integrates into the host chromosome and As stated earlier that there are number of viruses that have a is later expressed under the control of viral transcriptional tendency of natural tumor selectivity. Mullen and Tanabe[23] regulatory sequences. Once integrated, proviruses are stated regarding the direct and the indirect mechanism of rarely lost from the host chromosome. Normal cellular antitumor effect executed by the viruses. Either there is direct transcriptional and translational controls are lost once an lysis of the tumor cells due to the replicating viral vectors alone acquired cellular sequence is incorporated into the viral or in association with other modalities such as radiotherapy or genome. Overexpression of a proto‑oncogene under the , or the other mechanism refers to the indirect control of strong viral promoters can cause malignant amplification of antitumor immunity which is brought about by transformation.[17] modulation of the immune response. They have also discussed regarding the mechanisms of antitumoral efficacy, antitumoral Human T‑cell leukemia virus 1 specificity and effects of the immune response. Oncolytic The only currently accepted human tumor virus from Viruses present a different course of action for the retrovirus family ‑ Associated with adult T cell by acting as in situ vaccines and may use immunomodulatory leukemia/lymphoma (ATL). This virus carries oncogene transgenes. However, there may be negative outcome due to “tax” ‑ Tax protein: A transcription factor, function in viral restricted virus replication or dissemination in tumor tissue or replication, also responsible for enhanced transcription of due to induction of antitumor immune responses. According viral and cellular genes that promote cell growth factor and to Chiocca and Rabkin, certain aspects of the Oncolytic dysfunction of cellular regulatory tumor suppressor genes. Viruses‑tumor/host interaction are important in proving During the replication process, the virus uses an enzyme called the effectiveness of therapy such as degree of inflammation reverse transcriptase, which allows the virus to change its and innate immune responses, types of virus‑induced cell RNA genes into DNA. This allows the virus genes to become death, inherent tumor physiology, blood and lymphatics integrated into the genes of the host cell and can cause a supply, connective tissue architecture, tumor cell phenotype mutation in the host cell genes that control how the cell divides. and immunosuppressive factors expressions.[24] The various This change can sometimes lead to cancer. HTLV‑1 has been mechanisms include direct cell lysis due to viral replication, linked to a type of lymphocytic leukemia and non‑Hodgkin direct cytotoxicity of viral proteins, and induction of antitumoral lymphoma called adult ATL. immunity, sensitization to chemotherapy and and Transgene expression are shown in Table 5.[25‑27] Merkel cell polyomavirus Merkel cell polyomavirus (MCPyV) is a small, nonenveloped Tollefson et al. reported that E3‑11.6‑kDa Adenovirus death and dsDNA polyomavirus identified in 2008. It is the first protein (ADP) encoded by the E3 region is required to cause

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Table 4: Oncolytic viruses with tumors for which they that Adenovirus has its oncolytic nature and carries it off by are used or under clinical trial encoding IL‑12. The anti‑tumor activity of the IL‑12 treatment Virus Tumor was T cell‑dependent, requiring mainly CD8 (+) cytotoxic EBV Burkitt’s lymphoma T lymphocytes (CTL) in the effector phase. Additionally, Nasopharyngeal carcinoma intratumoral injection of Adenovirus leads to increased Lymphomas under immunosuppression response of cellular immunity, as demonstrated by the Hodgkin’s disease frequency of interferon (IFN)‑gamma‑positive cells in regional lymph nodes, and thus changes the tumor microenvironment to Subset of T‑cell lymphomas an immunologic activation state with enhanced expression of HBV HCC lymphocyte activation markers and cell adhesion molecules.[29] Human herpesvirus 8 Kaposi’s sarcoma Ras transformation and defects in type I IFN‑mediated antiviral Body cavity lymphoma responses are known to be the major mechanisms underlying [22] HSV Recurrent glioma viral Oncolysis.[30] Glioma and neuroblastoma and pancreatic cancer Kanai et al. have described number of advantages of oncolytic HSV over OV based on other viruses, which included:[28] and pancreatic cancer • It infects most cell types in a broad range of species Recurrent glioma • It is very cytolytic, so that one infectious particle can HPV Anogenital cancers, oral replicate and spread in a cell monolayer cancers (20%) cancers in patients with • Its genome is very stable epidermodysplasia verruciformis • Many nonessential genes contribute to pathogenicity and Squamous cell carcinoma of the skin replication in non‑dividing cells Measles virus Burkitt’s lymphoma • It has a large genome, allowing multiple, non‑essential Newcastle disease virus Metastatic solid tumors genes to be replaced (up to 30 kbp) with multiple Reovirus Bone/soft‑tissue sarcoma therapeutic transgenes Vesicular Human melanoma • Effective antiviral drugs are available to treat adverse events virus in patients. Pox virus Liver, colorectal, head/neck Peritoneal cavity, head/neck Various Oncolytic HSV vectors have already entered into [31] Adenovirus Head and neck (+ chemotherapy) Phase II/III trials for a variety of different cancers. Solid tumors, cervical carcinoma Direct cytocidal effect Maraba virus Lung, colon, melanoma Herpes simplex viruses type 1 (HSV‑1) are promising Picornavirus Neuroendocrine tumors, glioblastoma, therapeutic agents. They replicate in the tumor mass, spread melanoma and exhibit oncolytic activity via a direct cytocidal effect. In Parvovirus Glioblastoma addition, specific antitumor immunity is effectively induced Egypt 101 virus Advanced, unresponsive neoplastic by these viruses in the course of oncolytic activities.[32] HSV disease was studied by Toda et al. as an in situ cancer vaccine for the virus, (wild type, Terminal cancers; gastric, pulmonary induction of specific anti‑tumor immunity. They inoculated the nonattenuated) uterine cancers attenuated HSV vaccine and studied the induction of a highly EBV=Epstein‑Barr virus, HCC=Hepatocellular carcinoma, HBV=Hepatitis B virus, HPV=Human papillomaviruses, HSV=Herpes simplex virus specific systemic anti‑tumor immune response. CD8+ CTL activity was generated.[33] Table 5: Viral protein inhibits antitumoral mechanism Increased sensitization to chemotherapy and radiotherapy Mechanism Adenoviral genes modulating effect Oncolytic viruses can engender an increased sensitivity of Direct cytotoxicity owing to viral proteins E3 11.6kD tumor cells to chemotherapy and radiation therapy. For example, The E1A gene product of adenovirus can induce high E4ORF4 levels of p53 in cancer cells and thus render them susceptible Augmentation of antitumoral immunity to DNA damage from chemotherapy and radiotherapy. Cytotoxic T‑lymphocyte infiltration, killing E3 gp19kD Normal, nontransformed cells appear to be unaffected by E1A. Tumor cell death, antigen release E3 11.6Kd Interestingly, the adenovirus E1A gene product can sensitize Immunostimulatory induction E3 10.4/14.5, 14.7kD tumor cells to chemotherapeutic agents even in the absence of Antitumoral cytokine induction E3 10.4/14.5, 14.7kD functional p53 by an unknown mechanism.[34] (e.g., Tumor necrosis factor) Enhanced sensitivity to E1A Expression of therapeutic transgenes (e.g., Tumor necrosis factor) The ultimate mechanism by which oncolytic viruses Sensitization to chemotherapy Unknown (? E1A, others) mediate antineoplastic activity is by the expression of Expression of exogenous therapeutic Not applicable therapeutic transgenes inserted into the viral genome. These [28] genes equipped therapeutic viruses offer distinct advantages. There is viral amplification and thus in turn there is a the death of the infected cell by cell lysis. There is release simultaneous amplification in transgene expression. These of virions that leads to the lysis.[24,29] Kanagawa et al. stated amplified transgenes in turn have antitumor effect. For

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example, Andreansky et al. genetically modified HSV and modality were carried out in 1956 and 1972 in reference to introduced a transgene into the virus to construct recombinant adenovirus adenoidalpharyngeal‑conjuctival virus[43] and HSV‑expressing murine Interleukins for the treatment of mumps virus[44] respectively. intracranial gliomas in immunocompetent mice.[35] Natural selectivity for tumor cells Oncolytic virotherapy The cellular changes induced by the viruses have now have Oncolytic virotherapy is playing a promising role in the field been known to us since many decades. These changes are of . The great milestones in the field of cancer therapy quite similar to the changes induced during carcinogenesis. have been mentioned in Table 6. Exploitation of viruses firstly This aids us in deriving the conclusion that some viruses do began with the twentieth century. Clinical trials were carried have a natural preference that is, these oncotropic viruses out which involved transmission of bodily fluids containing can be used for oncolytic virotherapy. Newcastle disease viral particles to other cancer patients and then observing the virus,[45] reovirus,[46] Autonomous parvovirus[47,48] and vesicular result. Hepatitis viruses can be considered to be the pioneer stomatitis virus (VSV)[49] are few examples of the viruses with group to be used for therapy. Hoster et al. published his study natural tumor selectivity.[50] on association between Hodgkin’s disease and viral hepatitis. He observed in three of his patients with Hodgkin’s disease, Genetically modified viruses infection with viral hepatitis lead to the remission in two of the The other variant includes the genetically modified tumor cases with death being reported for the third case. Encouraged selective viruses. These are of great value in the treatment of by the improvement in the two cases he included further 21 cancer as they can be genetically modified with desired genes diagnosed cases of Hodgkin’s disease and studied the effect of that can put to use for appropriate results. When thymidine viral hepatitis in the remission of the disease.[10] Patients were kinase gene is deleted in Herpes simplex virus‑1 it forms diagnosed of developing viral hepatitis out of which 7 patients genetically modified HSV‑1 that is now oncolytic in nature. reported improvement lasting for at least 1‑month.[42] Other examples include that Poliovirus, Vaccinia virus, virus, etc.[50] Alice Moore pioneered the work of testing oncolytic viruses on animal cancer models. He along with Southam and Moore Systemic administration of oncolytic viruses contributed much to this vast field of oncolytic viruses A variety of pathways have been opted for the administration more in terms of transferring this notion from papers to of oncolytic viruses to the tumor site in the best possible way practicality. With special reference to Egypt 101 viruses, they so that maximum result can be obtained with least systemic tried to explore the antineoplastic properties of viruses. These destruction of viruses. There can be intratumoral or systemic viruses proved to be of limited value due the dangerous side administration of the viruses depending on various factors. For effect of neurotoxicity.[43] This has led to the gradual shift to example, death from cancer is often the result of inaccessible adenoviruses, paramyxoviruses, poxviruses, etc. Few milestone or metastatic disease, for this reason, systemic administration clinical trial in field of oncolytic virus being used as treatment of the oncolytic viruses is considered to be more effective than the intratumoral injection. However, even the systemic Table 6: Milestones in cancer virotherapy administration poses a threat of annihilation of the viruses 1842 Long performs under ether anesthesia[36] when recognized by immune cells as foreign antigen. Both the and any metastatic deposits can be treated 1895 Radiotherapy for cancer[37] simultaneously when intravenous route of administration is 1903 First cured case of cervical cancer by X‑rays[37] [38] chosen. Data from clinical trials have revealed that oncolytic 1942 Nitrogen mustards introduced as chemotherapeutics viruses can be safely delivered systemically. There is limited [39] 1948 Folic acid antagonists for treatment of leukemia toxicity but the results are equivocal in reference to efficacy, 1952 Salk developed particularly when delivered with adjuvant chemotherapy. 1958 First solid tumor cured by chemotherapy[40] A key reason for this could be the rapid clearance of the 1965 Simultaneous administration of drugs (POMP viruses from the circulation before they reach their targets. regimen) induces long‑term remission in ALL[41] This phenomenon of clearance of viruses from circulation is 1968 Stereotactic radiosurgery developed[21] mainly mediated through neutralizing antibodies, complement 2005 First approval of oncolytic virus[37] activation, antiviral cytokines, tissue‑resident macrophages, as 2006 FDA approves first HPV vaccine for use to prevent well as nonspecific uptake by other tissues such as the lung, cervical cancer liver and spleen, and suboptimal viral escape from the vascular 2010 Sipuleuce‑T (Provengel) therapeutic cancer vaccine compartment. Varieties of methods have been designed approved by FDA for prostatic cancer and reported in the literature to overcome these hurdles in 2011 ‑VF, a therapeutic cancer vaccine being preclinical models.[51] developed by Bavarian Nordic 2008-2014 GVAX, which was first created in 1993 by Glenn Measures for assisting spread of oncolytic viruses Dranoff Polymer coatings 2014 Modified measles virus produces durable tumor There are several strategies to prevent the sequestration of viruses regression in multiple myeloma[22] in the liver and spleen. Hydroxypropyl methacrylamide (HPMA) 2014 ProstAtak (AdV‑tk+valacyclovir), a virus‑based is a polymer that is used widely for stabilization of bioactive therapeutic cancer vaccine given along with an proteins thus modifying their interaction with biological anti‑virus drug environment.[52] These can also be used on biological surfaces such ALL=Acute lymphocytic leukemia, HPV=Human papillomaviruses, FDA=Food as virus, , etc. Other polymer that can be used include and Drug Administration

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PEG (Polyethylene glycol) and PGA (Polyglutamic acid).[53] In a such as digital transcriptome subtraction for discovery and study performed by Morrison et al., in which they used HPMA identification of viruses, it becomes easy and has increased polymer coated adenoviruses were used in the treatment of hope to use them against cancer. Oncolytic virotherapy is intraperitoneal cancer.[54] Eto et al. developed PEG coated gaining strength recently due to promising evidence from adenovirus vector with specific targeting ligands at the tip of PEG various clinical trials that have been undertaken in world which in turn increases the efficiency of the vector.[55] Alemany using Oncolytic viruses in past few decades as well which are et al. studied the blood clearance rate of adenovirus type 5 in currently undergoing. Oncolytic virotherapy is a promising mice. They compared the clearance between non polymer coated anti‑cancer strategy, because it can help in localization or and coated viruses. Adenoviruses in the blood are taken up by abolition of tumors without substantial side effects. The Kupffer cells (specialized macrophages) and are degraded. They first commercialized oncolytic virus, Oncorine that has concluded that both the clearance rate as well as infectivity was been approved by Chinese SFDA in November 2005 for reduced.[56] Both PEG and HPMA are used clinically to prolong nasopharyngeal carcinoma combined with chemotherapy. the circulation times of proteins and to reduce off‑target toxicities. Since then, a number of oncolytic viruses have been moved After intravenous administration, Level of viable adenovirus, in into clinical trials. These include the armed oncolytic plasma falls to <0.1% within 30 min.[57] adenoviruses such as H103 (expressing the heat shock protein) that has currently finished phase I trial and KH901 (expressing Sequestration of Kupffer cells GM‑CSF) has now been launched in phase II. The initial results It has been cited by Haisma and Bellu that intravenous of clinical trials using Oncolytic viruses are encouraging. There administration of low doses of adenovirus results in their are many Oncolytic viruses currently under development.[63] sequestration in liver due to binding to the scavenger receptor Three Oncolytic virus platforms (vaccinia, HSV and Reo) are on Kupffer cells. Hepatic cells also bind to adenovirus in blood in or entering phase III clinical studies. But because of their factor‑dependent manner. Various methods to eradicate the macromolecular nature and their ability to activate the immune binding to liver cells may include chemical modifications mechanism, they pose as an obstacle in their use for treatment of adenovirus to guard the capsid proteins, interfere of cancer as well as have detrimental side effects which needed binding to specific cell types and adenovirus capsid protein to be address adequately before putting into use on humans. mutations. These methods if followed results in the successful After First cancer vaccine development in 2006 in USA, vaccine [58] administration of oncolytic viruses to the tumor site. When development programs have taken new shape. Provenge, a adenoviruses are taken up by Kupffer cells, there is necrosis of cancer vaccine designed to treat advanced , has Kupffer cell that can be appreciated histologically. Studies have got approval from the FDA for use in the treatment of advanced shown that even after an initial intravenous injection of vector, prostate cancer patients in 2010.[14] dead Kupffer cells were unable to take up a second dose of vector, and hepatic transgene expression from the second dose Future Prospects was augmented. Thus, this concept of high‑dose administration [59] can be utilized for increasing the oncolytic viral load. Oncolytic virotherapy has good future as recent experimental findings have increased hope in research community about Use of carrier cells utilization of virus as anti‑tumors agent with combination Power and Bell (2008) hypothesized that carrier cells or the cells adjunct to the conventional treatment modalities such that are infected ex vivo, if infused intravenously then vectors as chemotherapy and radiotherapy or to replace them in would be protected from the defense cells of the body.[60] For future. Thought lots work still need to be done in this field, example, Power et al. delivered VSV using CT26 murine colon recent approval of tumor vaccine and oncolytic viruses by carcinoma cells that are readily infected by VSV to mice with FDA and Chinese SFDA has taken giant step toward bring established lung metastases. Microscopic examination revealed it in clinical application. There is a long and growing list the presence of VSV in tumor cells and also showed their of new or improved versions of oncolytic viruses. With absence in the surrounding normal lung tissue.[61] emergence new technology and understanding of OV and their role in the development of cancer, current obstacles Neovascularization in the development and full utilization of oncolytic viruses Tumors growth shows areas of neovascularization newly can be solved. formed immature blood vessels are leaky due to incompletely developed endothelial cells. 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