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Oncolytic ("onco" meaning cancer, "lytic"
meaning "killing") viruses represent an innovative potential cancer
therapy known as "virotherapy"—a therapy that seeks to harness
the natural properties of viruses to aid in the fight against cancer.
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The notion of using
a virus in the fight against cancer has existed for many decades.
In the 1940s and 50s, studies were conducted in animal models
to evaluate the use of viruses in the treatment of tumors. In
1956, one of the first human clinical trials with an oncolytic
virus was conducted in patients with advanced stage cervical
cancer. Although the results were promising, research in this
arena was delayed due to the lack of technology needed to purify
viruses as well as to safely deliver the viral treatment. It
was not until 1991, following a publication in Science
magazine about a study conducted at Georgetown University that
used the herpes simplex 5 virus for the treatment of brain cancer,
that new attention was focused on virotherapy.
In short, oncolytic viruses are human viruses that infect and
replicate in cancer cells, destroying these harmful cells and
leaving normal cells largely unaffected. Like all viruses, oncolytic
viruses seek to penetrate a host cell and "trick"
it into replicating more of the virus until ultimately, it bursts.
However, unlike other viruses, oncolytic viruses seek only to
replicate in cancer cells. |
"Non Engineered" versus "Engineered"
Oncolytic Viruses
Research is currently being conducted by institutions around the world
using both "non engineered" and "engineered" viruses
to evaluate their use in the fight against multiple types of cancer.
Non engineered viruses are naturally occurring viruses that innately
preferentially target and replicate in certain types of tumor cells.
Some non engineered viruses include the Newcastle Disease Virus, Autonomous
Parvovirus, and the Reovirus. Conversely, engineered viruses do not
innately selectively target and replicate in cancer cells. Scientists
must genetically modify ("engineer") the virus to selectively
target and/or replicate within specific types of cancer cells. Today,
there are three main approaches that are being explored in the development
of engineered tumor-specific oncolytic viruses. Although the three
approaches differ from one another, they all share a common goal—the
destruction of cancer cells as a result of viral replication. The
three approaches are as follows:
1. Selective Targeting—Capsid
Protein Modification: The capsid protein, the external surface
of the virus, is modified so that the virus will specifically target
cancer cells, completely avoiding normal cells. The virus would then
replicate within the targeted cancer cell, ultimately leading to cell
death.
2. Selective Replication in
the Absence of an Antitumor Gene: The virus is genetically
modified so that it will replicate only in the absence of a gene believed
to inhibit tumor cell growth, such as P53. While the virus "passes
through" normal cells, it is triggered to replicate in cancer
cells that do not exhibit an antitumor gene, ultimately leading to
cancer cell death.
3. Selective Replication in
the Presence of Unique Tumor Cell Characteristic:
The virus is genetically modified so that it will replicate only in
the presence of a characteristic (e.g. an antigen) unique to the specific
type of cancer. While the virus passes through normal cells, it is
triggered to replicate in cancer cells that exhibit a specific characteristic,
ultimately leading to cancer cell death. Cell Genesys' oncolytic virus
product platform utilizes this approach.
Examples of viruses that are engineered include the adenovirus, the
herpes simplex virus-1, influenza, and the vaccinia virus.
Destruction of Cancer Cells
Oncolytic viruses utilize multiple mechanisms of action to kill cancer
cells—cell lysis, cell apoptosis,
antiangiogenesis and cell necrosis. Once the virus infects the tumor
cell, it compromises the cell's natural defense mechanisms, giving
the virus extra time to thrive. The virus then begins to replicate.
The virus continues to replicate until finally the tumor cell can
no longer contain the virus and "lyses" (bursts) the host
cell's membrane. The tumor cell is destroyed and the newly created
viruses are spread to neighboring cancer cells to continue the cycle.
It is important to remember that all oncolytic viruses are intended
to replicate only in cancer cells and to pass through normal tissue
without causing harm. Hence, once all the tumor cells are eradicated,
the oncolytic virus no longer has the ability to replicate and the
immune system clears it from the body.
Possible Benefits of Oncolytic Virus Therapy
Clinical data suggest that oncolytic viruses may offer therapeutic
advantages over existing cancer therapies such as chemotherapy and
radiation. The three primary benefits identified to date include the
following:
1. High Therapeutic Index:
Compared with traditional therapies, oncolytic viruses have
been shown to have a high therapeutic index. In some instances, the
therapeutic index of oncolytic viruses has been found to be as high
as 100,000 to one. In other words, for every 100,000 tumor cells that
are killed, only one normal cell is killed. This is significantly
higher than the therapeutic index commonly seen with chemotherapy—six
to one—and may result in greater efficacy with fewer side effects.
2. Better Antitumor Efficacy
due to Viral Replication: Unlike some traditional therapies
that are cleared from the body within a specific amount of time (e.g.
chemotherapy), oncolytic viruses are engineered to proliferate and
remain in the body until all of the cancer cells are destroyed. This
self-proliferation could potentially mitigate the need for extensive
re-treatment and result in greater efficacy and patient convenience.
3. Synergistic Antitumor Activity
with Other Cancer Therapies: Some oncolytic viruses have been
shown to have significant synergy with conventional cancer treatments
such as radiation and chemotherapy. This type of combination therapy
could potentially lead to greater therapeutic efficacy.
The Current State of Oncolytic Virus Therapies
Research and development efforts are currently under way at numerous
organizations to thoroughly evaluate the safety and efficacy of oncolytic
virus therapies. The majority of the studies currently being conducted
are utilizing intratumoral delivery of the oncolytic virus therapies.
Direct administration into the tumor allows the oncolytic virus immediate
"access" to the cancer cells in which they replicate and
ultimately destroy. Additional studies are being conducted to determine
the safety and efficacy of intravenous administration of oncolytic
virus therapy. While intravenous administration holds the promise
of providing systemic treatment and targeting cells that have spread
from the primary tumor source, researchers are faced with the challenge
of maintaining therapeutic levels of the virus in the presence of
the immune system which intrinsically seeks to rid viruses from the
body. Intravenously administered oncolytic virus therapy must overcome
pre-existing antibodies in order to achieve therapeutic effect. Alternatively,
research is being conducted to determine a way to modulate the immune
response allowing the virus time to reach the primary tumor source
as well as target cancer cells that have spread throughout the body.
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