Incidence of cancer (excluding skin cancer) is 10,055.6 per 100,000 people and the mortality rate
is 6,208.7 per 100,000 people(1).Cancer is a complex disease and difficult to treat. The early
1900s produced significant advances in cancer therapy including surgery, radiotherapy,
chemotherapy and immunotherapy but none of them was applicable to all tumors at all stages.
Tumors could neither be removed surgically all the time nor be killed all the time with highenergy
beams of radiation or with poisons delivered to them intravenously. Even the
combination of these proved to be insufficient.
History and basis of virotherapy
The past decade has played a great role in our understanding of the genetic basis of human
diseases. Among them the most profound impact has been in the area of cancer genetics, where
the explosion of genomic sequence and molecular profiling data has illustrated the complexity of
human malignancies. This complexity often interferes with the therapeutic regimes. It is
reasonable to suggest that sophisticated therapeutics that can attack cancers in multiple, but
targeted ways, will be necessary in order to improve current success rates. The Oncolytic Viruses
(OVs), which have the intrinsic ability to selectively replicate in and kill cancer cells, have found
application in the treatment of primary and metastatic cancers with tremendous potential to
revolutionize the management of what has become one of mankind's disaster. A number of
viruses are being developed around the world for this purpose (2). The use of viruses in the
treatment of cancer was not by chance but rather was considered from the observation that,
sometimes, cancer patients who had an infectious disease went into brief periods of clinical
remission. In the case of leukemia, it was well recognized that influenza virus infection
sometimes produced beneficial effects (3,4). Although no cases were reported where an
accompanying infectious disease led to complete cure of leukemia, it was anticipated that the
treatment based on the causative agent may provide an alternative to the ordinary treatment of
The first clinical trials involved transmittance of body fluids containing viral particles to other
cancer patients and observing the result, without knowing their biological behavior. The viruses
were destroyed by the immune system and were eliminated from hence failed to destroy the
malignant cell growth. In the 1950’s and 1960’s, many attempts were made to develop viruses
with greater tumor specificity (5). The mouse sarcoma 180 could be completely destroyed when
treated with oncolytic virus proved to be a landmark for virotherapy (6). With a better
understanding of virology, as well as experience using viruses in cancer gene therapy, has
prompted a new wave of oncolytic virotherapy.The use of genetically engineered, tumor-specific
viruses as oncolytic agents recently has emerged as a promising method for cancer therapies.
ONYX-015 (an oncolytic adenovirus) was the first oncolytic virus which demonstrated both the
safety and anti-tumor potential of this approach (5).
Mechanism of antitumoral efficacy of oncolytic viruses
There are different mechanisms utilized by the oncolytic viruses to destroy the cancer cells. The
virus can destroy tumor cells by replicating. The initial infection of only a few tumor cells would
initiate a chain reaction and will cause the subsequent destruction of the surrounding tumor cells.
Once the virus reaches and infects the surrounding normal tissue, replication of a virus that is
selective for tumor cells would be aborted, sparing normal tissue. Moreover, this feature of
viralreplication provides continuous amplification of the input dose which continues until
stopped by the immune response or a lack of susceptible cells (6). Secondly some oncolytic
viruses synthesize certain proteins during their replication which are directly cytotoxic to tumor
cells. Thirdly they can initiate specific and nonspecific anti-tumor immune responses. It is well
known that the tumor cells are inherently weakly immunogenic because they express low levels
of major histocompatibility complex (MHC) antigens and stimulatory signals such as cytokines
which activate a local immune response.Adenoviruses express E1A protein during replication,
which mediates killing of tumor cells byincreasing their sensitivity to tumor necrosis factor
(TNF) (7). Viral peptides are presented on the cell surface with MHC class 1 proteins; this
complex is recognized by cytotoxic T lymphocytes (CTLs) and are attracted by the virallytransduced
tumor cell which intern can acquire specificity for tumor-specific antigens and kill
the cells by an unknown mechanism (6).
Fourth mechanisms by which oncolytic viruses can lyse the tumor cells are enhancing the
sensitivity of tumor cells to chemotherapy and radiation therapy. The adenoviral E1A gene
product is an example. It is a potent chemosensitizer in cells with functional p53. It can induce
high levels of p53 in these cells and make them susceptible to DNA damage from chemotherapy
and radiation. Normal, nontransformed cells remain unaffected. This gene product can sensitize
tumor cells to chemotherapeutic agents even in the absence of functional p53, though the
mechanism isknown yet (8).
A final mechanism by which oncolytic viruses mediate antineoplastic activity is by the
expression of therapeutic transgenes which is inserted into the viral genome. These
therapeuticviruses offer a specific advantage over the replication-incompetent viruses that have
been employed in the vast majority of gene therapy applications up till now. As the virus
replicates, there is a simultaneous amplification of the inserted gene expression, which intern
produces an amplified antitumor effect. Some researchers have inserted prodrug-converting
enzymes, such as viral thymidinekinase and bacterial cytosine deaminase (CD), into replicationconditional
adenoviruses to enhance tumor cell lysis(6, 8). Others have introducedvarious
immunostimulatory genes such as interleukins-4 (IL-4) and -12 (IL-12) into oncolytic herpes
viruses,hence attempting to augment the antitumor immune response of the tumor cell (6).
Development of oncolytic Viruses
Chemotherapy and radio-therapy are current mainstays to treat advanced cancers but have
limitations such as, tumor cells develop resistance to these agents and a relatively have
narrowtherapeutic index. Moreover, increased dose or combinationtherapies designed to
overcome this resistance or increase tumor cell lysis are limited by toxicity to normal
tissues.Oncolytic viral therapy, on the other hand, is able to increase the therapeutic index
between tumor cells andnormal cells when viral replication proceeds preferentiallyin tumor cells.
While using the oncolytic viral therapy to treat cancers the main challenge faced is the immune
system of the host. The use of rapidly acting, genetically engineered, tumor-targeting viruses are
a promising new area for novel cancer therapies (9). Following are the techniques to modify the
viruses and to enhance their clinical utility.
The virus should be able to tolerate storage and production at high titres. A double-stranded
DNA genome is advantageous because it has greater stability during storage hence reducing the
chances of hazardous mutations. Viruses like adenoviruses and herpes simplex virus are the most
suitable, and have been the most extensively used and studied.
Generating tumor selectivity
The oncolytic viruses can be made tumor specific and selective by transductional and nontransductional
Itinvolves modification of the specificity of viral coat protein, thus increasing entry into target
cells while reducing entry to non-target cells. This approach has mainly focused on adenoviruses,
although it is entirely viable with other viruses too. The most commonly used group of
adenoviruses is serotype 5 (Ad5), whose binding to host cells is initiated by interactions between
the cellular coxsackievirus and adenovirus receptor (CAR), and the knob domain of the
adenovirus coat protein. These receptors are necessary for adenovirus infection by showing that
CAR-negative cells could be made adenovirus-sensitive by transfection with CAR cDNA (9). In
addition the viralinternalization depends on an Arginine-Glycine-Asparagine (RGD) motif at the
base of adenovirus coat protein that binds to integrins, causing endocytosis. It has been suggested
that CAR has a role in cell adhesion, and possibly tumor suppression. Although expressed widely
in epithelial cells, CAR expression in tumors is extremely variable, leading to resistance to Ad5
infection. Retargeting of Ad5 from CAR, to another receptor that is ubiquitously expressed on
tumor cells (6,9), can be done in one of two ways explained below:
Specific adapter molecules can be administered along with the virus to redirect viral coat protein
tropism which are fusion proteins and are made up of an antibody raised against the knob domain
of the adenovirus coat protein, fused to a natural ligand for a cell-surface receptor. The use of
adapter molecules has proved to increase viral transduction. However, adapter molecules add
complexity to the system, and what effect is produced on the stability of the virus is uncertain
Genetic modification of the fiber knob domain of the viral coat protein is done to alter its
Ifshort peptides are added to the C-terminal end of the coat protein, successfully altersviral
tropism. The addition of larger peptides to the C-terminus is not viable because it reduces
adenovirus integrity,possibly due to an effect on fiber trimerisation. The fiber protein also
contains an HI-loop structure, which cantolerate peptide insertions of up to 100 residues without
any negative effects on adenovirus integrity (10). Insertionof RGD motif in the HI loop of the
fiber knob protein, shifts specificity toward integrins, whichOncolytic virus 4are frequently overexpressed
in Oesophageal Adenocarcinoma. When combined with a form of nontransductionaltargeting,
these viruses proved to be effective and selective therapeutic agents for
Oesophageal Adenocarcinoma (11).
It involves altering the genome of the virus so that it can only replicate in the tumor cells. This
can be achieved either by transcription targeting, where genes essential for viral replication are
placed under the control of a tumor-specific promoter, or by attenuation, which involves
deletions of the viral genome that results in the elimination of such functions which are
necessary for replication and cytolytic effects of that particular virus and are dispensable in
cancer cells, hence making the oncolytic viruses, tumor specific (6).
By using this techniqueessential viral gene is put under the control of a tumor-specific promoter.
It is well known that the gene is only expressed in cell types where all the transcription factors
required for promoter function are active. A suitable promoter should be active in the tumor but
inactive in the majority of normal tissue, particularly the liver, which is the organ that is most
exposed to blood born viruses. Different promoters have been identified and studied for the
treatment of a range of cancers. Cyclooxygenase-2 enzyme (Cox-2) expression is elevated in a
range of cancers, and has low liver expression, making it a suitable tumor-specific promoter.
Cox-2 is also a possible tumor-specific promoter candidate for other cancer types, including
ovarian cancer.Another suitable tumor-specific promoter is prostate-specific antigen (PSA),
whose expression is greatly elevated in prostate cancer. CN706 is a CRAd with a PSA tumorspecific
promoter driving expression of the adenoviral E1A gene, required for viral replication
(12). (See fig: A& B)
Cancer cells and virus-infected cells have similar alterations in their cell signaling pathways,
particularly those that govern progression through the cell cycle. A viral gene whose function is
to alter a pathway is dispensable in cells where the pathway is defective, but not in cells where
the pathway is active. Attenuation involves deleting viral genes, or gene regions, to eliminate
viral functions that are expendable in tumor cell, but not in normal cells. For adenovirus
replication, the host cell must be induced into S-phase by viral proteins interfering with cell cycle
proteins. The adenoviral E1A gene is responsible for inactivation of several proteins, including
Retinoblastoma, allowing entry into S-phase. The adenovirus E1B55kDa gene cooperates with
another adenoviral product, E4ORF6, to inactivate p53, thus preventing apoptosis. For
example,inAd5- 24E3, there is 24 base pair deletion in the retinoblastoma-binding domain of
the E1A protein, making it unable to silence retinoblastoma, and therefore unable to induce Sphase
in host cells. This means Ad5-24E3 is only able to replicate in proliferating cells, such as
tumor cells. Moreover, the herpes simplex virus genome contains the enzymes thymidine kinase
and ribonucleotide reductase, whose cellular forms are responsible for the production of dNTP’s
required for DNA synthesis and are only expressed in Oncolytic virus 5 during the G1 and S
phases of the cell cycle. These enzymes allow herpes simplex virus replication in quiescent cells,
so if they are inactivated by mutation the herpes simplex virus will only be able to replicate in
proliferating cells, such as cancer cells. A LacZ insertion in G207 herpes simplex virus mutant,
inactivates ribonucleotide reductase (6, 9).
The HSV-1 viral mutant d120 is deleted of the viral essential gene 4 and does not replicate
upon infecting cells. The transcriptionally targeted HSV-1 G92A was created by placing the 4
gene under the transcriptional control of the albumin enhancer/promoter elements and restricted
viral replication to albumin expressing cells. Wild-type HSV-1 replicated efficiently in cells
irrespective of albumin expression, while virus G92A replicated more efficiently in albuminexpressing
cell lines compared to nonalbumin-expressing cell lines. In a similar vein, the
calponin promoter has also been used to control expression of HSV-1 4. Calponin mRNA is
overexpressed in soft-tissue/bone tumors, thereby providing a means to target such tumors with
The drawback of the above-mentioned transcription-targeted approaches is that individualized
viruses have to be created for each tumor type. Also, tumors within a given tissue type also can
vary in their expression of specific transcription factors, limiting the utility of such viruses for
broad tissue types. To circumvent these problems, an adenovirus was constructed that targets
tumor endothelial cells. The benefits of targeting the tumor vasculature are twofold: genetic
stability and a common process among multiple solid tumors. The process of angiogenesis by
endothelial cells involves the upregulation of multiple endothelial cell receptor complexes such
as VEGF and tumor growth factor (TGF)-. By placing the adenoviral E1A and E1B genes under
the transcriptional control of the Flk-1 (VEGFR-2) and endoglin (CD105/TGF- receptor
component) promoter/enhancer sequences, the adenovirus preferentially replicates in dividing
endothelial cells compared to tumor cells (12).
Therapeutic Gene Delivery with Replication-Competent Viruses
Therapeutic Genes have been employed with replication-selective tumor viruses as well. These
strategies have included the delivery of immunomodulatory genes, prodrug-converting enzymes
(suicide gene therapy), and cytotoxic genes. Replication-competent HSV-1 has been created to
express the immunostimulatory IL-12 gene and the prodrug-converting enzyme cytosine
deaminase gene. Replicating adenoviruses have also been created that express the cytotoxic
TNF- gene and the genes encoding the prodrug-converting enzymes cytosine deaminase and
thymidine kinase. Delivery of a cytotoxic gene in combination with a replication-competent
virus seems counterintuitive. However, these approaches appear to augment the therapeutic
effect of antitumor therapy. The therapeutic gene delivered may enhance tumor cell kill by
eliciting a bystander effect and results in the cell death of neighboring tumor cells that are not
infected by the virus (9, 12).
Combination Chemotherapy/Radiotherapy with Replication-Competent Viruses
Finally, the researchers have also started to assess the utility of combining standard anticancer
agents with replication-competent viruses. Ionizing radiation enhances the therapeutic potential
of both replication-competent adenovirus and HSV-1 in part by increasing the replication
potential of the viruses. A variety of chemotherapeutic agents have also been reported to increase
the efficacy of replication-conditional adenovirus and HSV-1. Especially intriguing in this
treatment paradigm are results of a Phase II clinical trial for recurrent head and neck cancer
treated with E1B-deleted adenovirus (ONYX-015) in combination with 5-FU and cisplatin.
Preliminary results suggest that the chemotherapy augments the therapeutic effect of replicatingconditional
This is how knowledge of cell and viral molecular biology has provided the basis for the
construction of genetically engineered viruses that selectively replicate in tumor cells.Other
replication-competent viruses under study include Newcastle disease virus and parvoviruses.
Multiple clinical trials are underway to determine the therapeutic efficacy of the current
generation of replication-conditional viruses. At the same time, further basic science research in
both tumor and viral biology is providing means to create more potent oncolytic viruses with
increased safeguards to specifically target the tumor. Most of the current studies have focused on
the use of replication-conditional viruses for regional therapy (i.e., direct tumor inoculation);
however, studies are also evolving that use of the virus as a systemic therapeutic agent could
target metastases too. This would involve the virus surviving the systemic circulation and then
homing in on malignant cells. Such viruses could bind selectively to tumor-cell-specific
receptors to gain entry and have their gene expression driven by tumor-cell-specific transcription
The Clinical Trials of the oncolytic viruses and their Success Rate
Oncolyticvirotherapy has success to some extent, even at this initial stage. Herpes virus,
adenovirus and many others are being evaluated in ongoing clinical trials for intractable cancers
(13). The very first viral therapy used for cancer treatment is adenoviral therapy and the virus
used is ONYX-015. ONYX-015 is a manipulated adenovirus that lacks the viral E1B protein
.in the absence of this protein, the virus is not able to replicate in cells with a functioning
p53pathway as mentioned earlier. In most tumors, this pathway is defective or non-functional
due to mutations, thus allowing ONYX-015 toreplicate and lyse the cancer cells (13). In
squamous cell carcinoma of the head and neck, ONYX-015has been used in phase I and II trials,
resulting in tumor regression which is correlated to the p53 status ofthe cancer. Tumors with an
inactive p53 pathway had a better response. ONYX-015, when used in combination with
chemotherapy in phase II, showed better tumor response, leading to phase III trials (14).
In addition, ONYX-015 is now a day being evaluated as a preventive treatment for precancerous
oraltissue, as in precancerous cells, p53 pathway-inactivating mutations will allow ONYX-015
todestroy and eliminate the precancerous cells before the tumor develops(15).
The virusCV706, in which the prostate-specific antigen (PSA) gene promoter-enhancer element
is insertedupstream of E1A gene is another adenovirus. It replicates specifically in tissues with
high PSA expression(15). This viral vector is being evaluated in a phase I/II dose-escalation trial
of intra-prostatic injection in patients with non-metastatic recurrent prostate carcinoma after
definitive radiotherapy. Results have shown that this treatment hassignificant anti-tumor activity
Gene manipulations in the viruses ensure their tumor specificity. NV1020,has various mutations,
including a deletion in the thymidine kinase region and a deletion across the long and short
components of the genome, moreover an insertion of thymidine kinase gene under the control of
the 4 promoter (6). G207 is mutated in such a way that it has attenuated neurovirulence and is
not capable of replicating in non-replicating cells (6). These viruses have different cell targeting
mechanisms. The lytic portion of the cell cycle kills cellsdirectly, and the thymidine kinase that
is expressed from the viral genes sensitizes cells to ganciclovir. Theyhave been tested in animal
models and in vitro against awide range of solid cancers successfully. G207 is being tested in
treatment of malignant glioma in a phase Iclinical trial; NV1020 is in phase I and phase II
clinical trials for the treatment of colorectalcancer metastases to the liver. This virus has also
been evaluated for the treatment ofglioblastoma(16).
Table 1. Partial list of oncolytic viruses in clinical trials, Adapted from Viral Oncolysis. John T,
Mullen, Kenneth K, Tanabe, The Oncologist 2002; 7:106-119..
OncoVEXGM-CSF is a 2nd generation oncolytic herpes simplex type 1 virus, encoding human
GM-CSF. OncoVEXGM-CSF represents an improvement over previous vaccine and virus-based
therapies for the treatment of cancer, as has been genetically reprogrammed to attack cancer cells
only. The insertion of the gene for human GM-CSF into the viral genome enhances the antitumor
response both locally and at sites located distant. Expression of GM-CSF in the local tumor
environment serves to achieveseveral biologic goals:
(a) induces local inflammation,
(b) enhances dendritic cell activity,
(c) producesantiangiogenic effect,
(d) increases HLA class II expression
OncoVEXGM-CSF was easily added to a standard chemoradiation regimen along with each
cycle ofcisplatin, without significant additional toxicity being observed (16)
Reovirus (respiratory enteric orphan virus) is a double-stranded RNA virus and is associated
with mild upper respiratory infections or enteritis. Reovirus infection results in activation of
transcription factors (NFB), MAP kinase pathways, and cell-cycle arrest, as well as apoptosis.
As it is a double-stranded RNA virus, replication of the viral genome activates double-stranded
RNA-activated protein kinase (PKR). Activated PKR phosphorylates the translation initiation
factor, eIF-2, resulting in the cessation of protein synthesis. For the viral replication, the actions
of PKR need to be stopped or inhibited. This can be achieved by activating mutations in the Ras
signaling pathway by transfecting genes encoding proteins that activate the Ras pathway, i.e.,
EGFR, v-erbB oncogene, or SOS. Ras activation induces an inhibitor of PKR (16).
Table 2. Oncolytic viruses and their advatages and disadvantages when used for cancer therapy ,
Adapted from Viral Oncolysis. John T, Mullen, Kenneth K, Tanabe, The Oncologist 2002;
Thirty percent of human tumors have Ras-activating mutations. Tumors having such mutations
would be predicted to permit reovirus replication. Initial results in tumor models appear to
support such a hypothesis. Tumors with activated Ras (i.e. gliomas, colorectal, and ovarian
cancers) are sensitive to reovirus infection. The interest in reovirus oncolytic therapy rests in its
natural safety profile and lack of associated disease pathology upon wild-type reovirus infection
Vesicular stomatitis virus (VSV) a rhabdovirus, consists of 5 genes encoded by a negative sense,
single-stranded RNA genome. In nature, it infects insects as well as livestock and causes a
relatively localized and non-fatal illness. Since VSV undergoes a rapid cytolytic replication
cycle, infection leads to death of the malignant cell and roughly a 1000-fold amplification of
virus within 24h. VSVis therefore highly suitable for therapeutic application, and several
researchers have shown that systemically-administered VSV can be delivered to a tumor site,
where it replicates and induces disease regression leading to durable cures most of the time.
Attenuation of the virus by engineering a deletion of Met-51 of the matrix protein ablates
virtually all infection of normal tissues, while replication in tumor cells is unaffected. Recent
research has shown that this virus has the potential to cure brain tumors (18- 20).
Viruses are able to target and kill cancer cells in human cancer patients. Cancer gene therapy is a
field which is progressing and attaining maturity very rapidly. No doubt oncolytic viruses will be
a part of future cancer therapies. Researchers are making efforts to over come the challenges
which are faced in the viral therapy. With the advancesin genetic engineering and biotechnology,
a number of viruses are being processed and modified to produce virus with improved safety and
efficacy. Various clinical trials are being made in different types of cancers. Most of these
clinical trials have had good results with high success rates using oncolytic virotherapy, and
many more clinical trials are in progress with new viral vectors for the treatment of untreatable
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