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 Sciences in the University of Bradford Division of Biomedical Sciences School of Life Sciences University of Bradford Bradford DATE of SUBMISSION: 28 th February 2013 WORD COUNT: 3350 Project Supervisor: Dr.J.Boyne
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Dissertation-Use of Oncolytic Virus as Therapeutic Strategy
This is a final year dissertation in the area of cancer biology. This dissertation discusses the use of oncolytic viruses and possible uses in the cancer therapy. It is a very interesting area of research as the usage of virus ,which normally causes harm to humans, might hold important key to cures. Of course, this dissertation is not possible without the guide of Dr.Boyne, my supervisor, from University of Bradford and my Cancer Biology lecturers from MDIS. References are included.
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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
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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