dissertation-use of oncolytic virus as therapeutic strategy
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Title: Use of oncolytic viruses as therapeutic strategy for cancer
A dissertation presented by:
Name: Farhath Jabien
Student number: S8706517J
UOB: 09034657
Batch code: BBSD1 1012A
For the BSc (Hons) in Biomedical Sciencesin the
University of BradfordDivision of Biomedical Sciences
School of Life SciencesUniversity of Bradford
Bradford
DATE of SUBMISSION: 28th February 2013
WORD COUNT: 3350
Project Supervisor: Dr.J.Boyne
Abstract:
Cancer is one of the deadly diseases in the world, claiming millions of lives. There
are many reasons behind the complications which cancer putforth to the medical
field.With improvement of knowledge of oncology and biotechnology, researchers
have begun working on creating a novel therapeutic strategy, with minimal side
effects. One of which is the usage of oncolytic viruses against cancer cells. The
oncolytic viruses are able to take advantage of cancer cells strengths and break
through several obstacles to infect and lyse the tumour. Moreover, with own
intelligence and capabilities or with man-made modifications, the ‘foe’ which causes
many deadly diseases or even cancer, can now be trusted as ‘friend’. The once
forsaken research in 1950s, has now steadily gained confidence and funding to carry
out more experiments and even clinical trials. This article aims to introduce the
‘rescuers’ of cancer and what are the mechanisms by which they operate, inclusive
of clinical trials.
Introduction
Cancer is one of the major causes of death worldwide, accounting for about 13% of
all deaths worldwide. (WHO, 2013) The causes of cancer could physical, chemical
or biological carcinogens. Examples of physical carcinogens are excessive, harmful
ultra-violet or ionising radiation. Examples of chemical carcinogens are tobaccoor
coal smoke, alcohols, aflatoxins and asbestos. Examples of biological are parasites,
bacteria and viruses. Chronic illness and genetic inheritance also contribute to tumor
formation.
Amongst various reasons, pathogenic, cancer-causing viruses alone give rise to
estimated 11% of total cases of death due to cancer. (Parkin,D.M.,2002) Some
examples of such viruses are, Epstein Barr virus causes Burkitts Lymphoma, Human
Herpes virus-8 causes Kaposi Sarcoma and cervical cancer is caused by Human
Papilloma virus.
Over the years, the medical field has fought hard against time and complexity of
cancers, to create a conventional, prescribed course of medical treatment. The
treatment consists of chemotherapy, radiotherapy, immuno-therapy, surgery or any
combination. However, the treatment is severely challenged and becomes failure due
to narrow therapeutic index and side effects. Moreover, treatments have very high
probability of incomplete eradication of invasive primary tumor cells or
dissemination of cancer cells. As such, there is a greater need for more effective
modalities.
The improvement of biotechnology and understanding of oncology, scientists are
thriving towards usage of virotherapy and gene therapy. As such the oncolytic
viruses are created using genetic engineering. (figure 1)
Figure 1: overview of mechanisms on oncolytic virus.Nakashima,H. et al.,(2010) Directing systemic oncolytic viral delivery to tumors via carrier cells Cytokine & Growth Factor Reviews .21(2) , 119-126
What are oncolytic viruses?
Oncolytic viruses are either naturally occuring or genetically modified viruses
designed to kill cancer cells, without harming the normal cells. The viral genes act as
tumor destructive agent and the capsids act as nano-sized nucleic acid delivery
vehicle. (Wakimoto, H et al.,2002) The oncolytic viruses operate via several
mechanisms which will be discussed in later sections.
Types of oncolytic viruses:
Enveloped/non-enveloped
Viruses which are classified as enveloped are ones that use the lipid bilayer of the
cancer cells and form a coat around them. An example would be viruses from the
Pox family, such as vaccinia virus or Paramyxovirus family, such as Measles virus.
The advantage of enveloped virus is that the glycoproteins present at the surface of
virus could detect and bind to specific receptors on cancers. Two main
glycoproteins are Hemagglutinin and Fusion proteins. The prior helps in attaching to
receptors and the latter aids in fusion of virus and the host cell like cancer cells.
Also, it was noticed that enveloped viruses could utilize larger specificity domain
like that of a single-chain antibody. (Cattaneo,R., 2010)
Genome(single/double stranded + DNA/RNA)
There are various types of viral genomes. Some are double stranded DNA like
adenoviruses and Herpes simplex viruses. Some are single stranded DNA viruses
like Parvoviruses. Examples of double stranded RNA viruses are reoviruses and
single stranded RNA are poliovirus (positive –stranded) and paramyxovirus like
measles virus (negative-stranded).
Natural /genetically modified
Naturally occurring viruses mean the virus requires no addition of genes
Generalized mode of actions of oncolytic viruses
In general, there are a few ways by which the oncolytic viruses work. Some of the
oncolytic viruses are designed or chosen to manipulate frequent tumour-specific
mutations, some are engineered to target signalling pathways and transcriptional
mechanisms that are ‘turned-on’ in tumours and some are aimed at antigens that are
overexpressed or unique on tumor cells. Despite the different mode of action, the
ultimate function of the oncolytic viruses is to disrupt the cancer cells’
transcriptional or translational mechanism and cause apoptosis.(Parato,K.A et
al.,2005)
Direct cell lysis:
Direct cell lysis is carried out by naturally occuring or selective-repllicating
viruses.The aim of this mechanism is to replicate and multiply inside the cancer
cell and lyse. Firstly, the viruse would adsorp to a receptor on cancer cell
membrane and creates a path through to penetrate its genetic materials to the host.
The genetic material would intergrate with that of the cancer cell genome. The
virus then uses the cancer cell’s replicating machinery to amplify viral
components. Then maturation and lysis occurs when there are surplus of viral
components, many progeny are created. The new virions then produce lytic
enzymes and burst the cell or activate apoptotic pathways by generating death
proteins to induce cell death. (Nakamouri,M.et al., 2004) (Figure 1)
Figure 1: The lytic cycle of viruses such as HSV-1 or adeno viruses shows the various stages of infection.
Adapted from source: Chiocca, A.E., (2002) Oncolytic viruses .Nature Reviews Cancer( 2), 938-950
An example of experiment involves Herpes Simplex Virus (HSV) against murine
colorectal carcinoma cells. It was observed that there was a trigger of tumour-
specific immune response and reduction in size. (Nakamouri,M.et al., 2004)
Anti-tumour mechanisms:
1) Targetting tumour environments:
a) Anti-angiogenesis:
Angiogenesis is one is the hallmarks of cancer. (Hanahan.D.,
Weinberg.R.A.,2000).Cancer cells are able to form their own blood vessels by
secreting growth factors like VEGF. Normally, in a mass of tumor, the inner most
cells (core region) are deprived from oxygen and nutrients. Therefore, such survival
technique is used.
Oncolytic viruses are designed to trigger loss of blood flow to the core of tumor,
causing depletion of oxygen supply (hypoxia) and nutrients. Inhibition of blood flow
is done by blocking the synthesis of growth factors by viral genomes. Lack of blood
flow would induce apoptosis in cancer cells, exempting normal functioning cells.
(Caroline et al.,2007) In a research experiment, vaccinia virus was used, with
deletion of thymidine kinase and and its own growth factor, to reduce pathogenicity
to normal cell. The virus was incorporated with soluble vascular endothelial growth
factor (VEGF) receptor –Ig fusion protein (monoclonal antibody). to demonstrate
anti-angiogenic effect (figure 2) (Guse.K et al.,2010)
Figure 2: Diagram of how vaccinia virus perform anti-angiogenesis
Adapted from:Kirn,D.H. and Thorne,S.H., (2011) Targeted and armed oncolytic poxviruses: a novel
multi-mechanistic therapeutic class for cancer.
Moreover, another oncolytic virus,adeno virus has been used to inhibit angiogenesis
is cancer. The adeno virus strain dl922/947 of serotype 5 and which is replicative,
had deletion of CR-2 region in E1A, which binds to cellular retinoblastoma protein
(pRB)*. The deletion of E1A CR-2 region* in the strain was crucial in order to
ensure that viral replication is only in cancerous cells. Concurrently, another strain
of adeno virus Ad-Flk1-Fc*, which was replication-deficient, encoding soluble
VEGF receptor antibody, was used to co infect the tumour cells. The dl922/947
strain became a helper virus and rendered its support by providing E1* functions in
trans to Ad-Flk1-Fc strain, which increased in strength. The end result in vivo was
desirable as anti-tumor and anti-angiogenic effect was observed as Ad Flk-Fc
replicated successfully, intratumoral levels of Flk-Fc proteins increased and
microvessel density declined. (Thorne.S.H., et al., 2006)
b) Anti-tumoral immunity induction
The immune system has two types of defense mechanism. One is non-specific or
innate while the other is adaptive. The innate immune system recognises foreign
particles and release 1st line defense molecules like neutrophils and other pro
inflammatory molecules. Then a complement cascade gets activated. On the other
hand, adaptive immune system holds the postiton to eliminate pathogens in late
phase of infection and creates memory cells after being triggered by presentation of
antigen presenting cells (APC) like macrophage and dendritic cells, from the innate
immune system.
One of the major barriers for oncolytic viruses is to fight against effectively or evade
promptly from the immune cells.under normal circumstances, despite antigens being
present on tumour epitopes, the efficiency of CD8+ T cells* was insignificant, due
to strong immunosuppressive environment around tumours.(Cerullo,V. et al, 2010)
Oncolytic viruses are found to have the capacity to alter tumour microenvironment
via oncolysis with release of molecules like tumour-associated antigen (TAA),
tumour-derived cytokine, viral nucleic acid, viral coat proteins which trigger
immune response. ( Hall,K.et al,2012) Therefore, to activate the immune system to
destroy tumour, a significantly strong firing must be released, to override the
defense set by the tumour,by the oncolytic virus.
In an experiment, HSV-derived strains (Fus-On-H2, Synco-2D, Baco-1) were used
to observe antitumour immunity in neuroblastoma cells which displayed Ras
signalling. It was noted that there was significant in vivo antitumour response and
destruction of cells in in vitro and omission of growth of new tumors at areas further
from viral-introduction site. Moreover, the strains were able to induce a strong
inflammation, leading to possible maturation of dendritic cell, which is needed to act
as antigen-presenting cell to signal cytotoxic T cells. Such weakening of the
“firewall” created by tumour, would be favourable to the host as they would be
infiltration of more immune cells to degrade tumour. (Li,H. et al 2007)
Another example would be the experiment done on adeno virus strain Ad-D24-
GMCSF, which is p16-Rb pathway* selective and had its E1 region removed and
had granulocyte macrophage colony-stimulating factor (GMCSF) incorporated into.
GMCSF aids in attracting natural killer cells to act directly on tumor and dendritic
cells which would recruit cytotoxic T cells, signalling from lymph nodes. The
tumour would be more vulnerable to the immune cells and it could be degraded.
Tumour cells’ immunologic tolerance was weakened as Ad-D24-GMCSF replicates
within tumour and was able to present survivin* as epitope, gaining the attention of
T cells. (Cerullo,V. et al 2010)
There is another method by which the oncolytic viruses ‘cruise’ through the sea of
immune defence molecules. The usage of T-cells as cheperones* to escort viral
vectors into tumours was tested on a research. T-cells have the capability of tumour
homing. Therefore, a replication-defective retroviral vector, which was incorporated
with apoptotic chemokines, was able to reach its target in tumour cells. (Kottke,T.et
al, 2008)
Adding on, another interesting mode of effectively evading immune system attack
and traveling through systemically to tumour site was the the clever tactic of
naturally occuring virus, vaccinia, a member of Pox virus family. It exists as
external-enveloped virion*(EEV), whereby it would be engulfed in lipid bilayer like
its host cell and would be released into the system at early stage of infection. This
was seen as a great advantage because the virus was able to “pretend” it was part of
the tumour as it could use the tumour’s outer lipid membrane as a ‘cloak’ and was
able to infect more tumour cells. Therefore, there was increased biodistribution of
virus within tumor and its microenvironment. Besides intratumoural infection,
intertumoural spread was more prominent. As such, metastatic tumours were could
be reached ( Kirn,D.H.,et al, 2008) (figure 3).
Figure 3: anti-tumoral immunity induction.
Source adapted from: Choi, I.K. and Yun,C.O., (2013) Recent developments in oncolytic
adenovirus-based immunotherapeutic agents for use against metastatic cancers Cancer Gene Therapy
(20), 70–76
c) Cytokines and signalling pathways:
IFN pathway:
Cancers often result from defective major signalling pathways which control normal
cellular functions, proliferation, immune response or programmed cell death
(apoptosis). An example of an important cascade is Interferon (IFN) pathway.
Interferons (IFN) are versatile cytokines which activate transcription of genes whose
products are mainly antiviral, anti-proliferative or immunomodulatory in function.
(de Veer.M.J et al., 2001)
For example, a type 1 cytokine, IFN-is produced due to viral infection, as first
line of defense to protect normal neighbouring cells. (Li.Q. and
Tainky.M.A.,2011). The IFN- increases the expression and transcription of IFN-
stimulated anti viral genes (ISG), such as IFN- and double stranded RNA-
dependent protein kinase (PKR). The ISG molecules influence the inhibition of viral
genome replication and protect neighbouring cells. (Saloura.V. et al.,2010)
However in tumour, cancer cells, due to mutation of type 1 IFN pathway, an
oncolytic virus could take advantage of the defect and replicate.
In a research, it was observed that PKR-null mice were highly susceptible to VSV
infection. (de Veer.M.J et al., 2001) The reason being, PKR in normal cell would
phosphorylate translational initiation factor eIf2a, which inhibits cellular translation
and prevents host and viral protein synthesis. Upon omission of PKR, virus could
synthesize proteins and carry out cytolysis. (Saloura.V. et al.,2010)
Moreover, in another experiment, with respect to disrupted IFN signalling pathway,
it was observed that two important Interferon regulatory factors (IRF)* 5 and 7 plays
a crucial role in making a cell susceptible to VSV infection.
In normal cell, IFN pathway has several important functions such as obstructing
viral replication, activating immune cells, increasing or up-regulating antigen
presentation to T cells, keeping uninfected cells safe. However, in cancer cells, the
IFN pathway is unregulated as IRFs are silenced. Thus, anti-proliferation and cancer
surveilance by the immune cells are halted.
d) Apoptosis-induced oncolysis:
The p53 protein is a very important protein that is the name “guardian of the
genome” is given. (Rao, B. et al., 2010) The p53 protein and a transcriptional
factor, plays a crucial role in cell cycle check points and behaves as tumour
suppressor, ensuring the genome is tightly conserved.
Cancer cells have a defect in apoptosis mechanism, which is the reason why there
is an increased cell proliferation and no programmed cell death. However, it was
found that more than 50% of tumours express the wild-type p53. Yet, the cancer
cells inhibit the function of p53 by several mechanisms. (Koo,T. et., 2011) It has
been observed that despite having a defective p53 signalling pathway, the
pathway could be restored. (Chipuk,J.E. et al., 2004)
An experiment was conducted to research if oncolytic viruses could restore wild-
type p53 functions in tumour cells. Tumour cells are found to have
overexpression of Mdm2 molecule which is a proto-oncoprotein and a negative
regulator of p53. As such, p53 would be degraded, allowing cancer cells to
multiply non-stop and escape apoptosis. Thus, using replicative-competent
adennovirus strains (which were modified at either C or N terminus* which had
p53 gene (variant and wild-type) incorporated within, tumours cells were
infected. The outcome showed efficient transcriptional activity of p53 and Mdm2
inhibitory effect on p53 was observed. Therefore, with functional p53, apoptotic
molecules like Bax from Bcl-2 family could be upregulated and apoptosis could
occur. (Koo,T. et., 2011)
Another experiment done on the famous Onyx-015 strain of adenovirus which had
E1B protein* removed. It was observed that irregardless of p53-deficient or p53-
mutated cancer cells, the Onyx-015 could infect and trigger apoptosis to occur.
Clinical trials:
Clinical trials are very important part of a research for a novel therapeutic
modality. The reason being, laboratory results are based on animal models, whose
immune system could be compromised in order to study any pathway and
behaviour of the oncolytic viruses, even when human tumor cell lines are to be
used, most experiments are done in vitro to avoid any unwanted reactions within
a host.
There are 4 main phases under clinical trial. Under phase 1, maximal dose and
pharmacokinetics are the focus. In phase 2, the dose-response, type of patients,
frequency of dose and efficacy is observed. Phase 3 is more on submission of
paper works and formalities, to obtain permission from Drug regulation
authorities of the country. Phase 4 would be last one, where product can be
marketed. A clinical trial has to follow many rules and strict regulation as to
comply to medical ethics. There are some key factors to abide to during clinical
trials.
Volunteers:
The sample size of the number of test subjects to be used and drawing out
eligibility of the test subjects is very important (Geletneky et al.2012).The
volunteers should not have any other medical problems that would affect the
administration of the viruses and they should be well versed with the aim and
procedures of the trials. They must be withdrawn upon any major complications
and adverse effects.
Standards:
Most clinical trials compare data by following the response evaluation criteria
soild tumour (RECIST). The sum of biggest diameter of the target tumour is
measured. Also, partial response, complete response, progressive disease, stable
disease, immune cell counts are all factors that would determine if the therapy is
effective. (Van der Veldt, A.A.M. et al., 2010)(Li, J.C. et al., 2008)
Aim:
a) Primary:
Firstly, the safety and tolerability of the investigational medicinal product (IMP)
is important. Researchers need to find out the maximum tolerance dose for each
oncolytic virus therapy used. Then, the maximum tolerance dose is calculated. It
relates to determining whether prolonged use of the therapy would cause any
adverse effects to the mass. Normally, an estimated maximum dose is given to
reduce number of test subjects and cost of administration.
b) Secondary:
The antitumour efficacy is monitored via tests like tumor markers, Computered
Topography (CT) scan, cytokines assay. Also, the survival of the test subject and
the period the subject is free from progression or recurrance is recorded.
Till date, there are several clinical trials after the re surfacing of research of
oncolytic viruses.
Phase I:
The first trial of ParvOryx, a Parvovirus H-1strain, was carried out on patients
with recurrent Glioblastoma Multiforme (GBM) which is high-grade gliomas.
The oncolytic virus was administered intravenously to study the systemic delivery
and gather data to serve as platform for future trials. (Geletneky et al.2012)
In another trial, JX-594, a pox virus strain with Thymidine kinase gene removed
was used against Hepatitis B virus which causes Hepato cellular carcinoma
(advanced refractory stage). The pox virus is relatively well-tolerated as there is
previous exposure to most people who have encountered ‘chicken pox’ by
varicella zoster virus. The dose was injected intratumorally. The host cells
retained thymidine kinase gene to allow replication of the oncolytic virus. The
outcome of the result was satisfactory as distal tumours were also targetted
despite presence of large number of antibodies.
PhaseII:
An example of phase II trial consists of replication-competent adenovirus strain,
Onyx-015. It was tested against squamous cell carcinoma of head and neck
(SCCHN). It was observed the virus remains in the blood stream for only a short
time and some discomforts of pain at site of injection and mild fever was felt by
the test subjects. (Nemuaitis,J. et al., 2001)
Phase III:
Reolysin is commercial product of Oncolytics Biotech, is a name for reovirus
strain, in combination with two drugs, Paclitaxel and Carboplatin. Being able to
clear phase II would mean that the therapy was efficient in reducing tumour size
and maximal dose has been determined. (Net resources international, 2012)
Adding on to the list of victory, OncoVex GM-CSFby BioVex company, a strain of
HSV-1 with genetic modification, has also progressed to phase III. In phase II,
the tumour size reduced to more than 50% (melanoma). OncoVexGM-CSF was able
to infect cancer cells and replicate and lyse, recruiting immune cells to clear out
the debris. As a strong oncolytic virus, it has shown remarkable results in breast ,
pancreatic, head and neck cancer and melanoma. With no modifications and tests,
the strain stands a great chance to tackle more cancer types. (BioVex Inc, 2012)
Conclusion
There are several types of oncolytic viruses with various types of mechanisms by
which they function. However, there are several drawbacks and contradictions and
problems laying which each experiment done. For instance, there could transient
viremia, where by the oncolytic virus is removed from blood stream quickly before
it could exert its impact or there could incomplete incorporation of viral genome
with the cancer cell, failing to turn on apoptosis . Despite these drawbacks, there is
hope that oncolytic viruses would be a novel therapeutic strategy earlier than once
expected.
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