- Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells without harming normal cells, while simultaneously stimulating the immune system and creating antitumor immunity. - Early observations in the early 1900s found that some cancer patients experienced tumor regression after acquiring viral illnesses, which led researchers to hypothesize that genetically engineered viruses could be used to treat cancer. - Since the first OV entered clinical trials in 1996, various OVs have been successfully tested against many cancer types and numerous clinical trials are currently evaluating their efficacy and safety.

1. Oncolytic Virus Basis
The strategy implementation of immunotherapeutic for the treatment of cancer has
gained prominence over the past decade in preclinical development and clinical
practice. Traditional oncological treatments, including surgery, radiation, and
chemotherapy, aim to directly remove or kill cancer cells, but receive high probability
of recurrences or serious side effects. In contrast, immunotherapy seeks to enhance the
host immune system’s ability to eliminate cancer cells, contributing to tumor
regression, antitumor immune memory formation, and ultimately durable responses.
There has long been interest in innovating an approach by which tumor cells can be
selectively and specifically targeted and destroyed. Surprisingly, Oncolytic viruses
(OVs) are viral strains that can infect and kill malignant cells without harming normal
cells, while simultaneously stimulating the immune system and creating antitumor
immunity.
Figure 1. The anti-tumor mechanism of oncolytic virus
Brief history of oncolytic virus
Although viruses have been utilized as therapeutic agents in the form of vaccines since
the late 1700s, their potential application as a cancer therapy was not explored until a
series of earliest clinical references reports were published dating back to the early
1900s, when several cancer patients were relieved after concurrent infection with
naturally-acquired viral illnesses. The first documented case of viral infection-induced
regression was in 1904 when a 42-year old woman with chronic myelogenous
leukemia experienced a marked reduction in white blood cells during a flu-like illness.
In another case, a four-year old boy with leukemia demonstrated a remarkable
remission after acquiring chickenpox. Unfortunately, after a one-month remission, his

2. leukemia relapsed and progressed rapidly to death. These observations led to the
hypothesis that viruses, in particular genetically engineered viruses, were
immunogenic and might be employed in the treatment of cancer.
Whereafter, a variety of different tumor types (including leukemia, cervical cancer,
lymphomas, solid tumors, melanoma, and multiple myeloma) and viruses (including
rabies virus, mumps virus, measles virus, adenovirus, parvovirus, and Newcastle
disease virus) got involved in tentative oncolytic therapies (Figure 2). Although some
patients experienced short-lived clinical remission of their cancers, a notable
proportion either died from the side effects of the viral therapy or had the brief
remissions that were reversed by a strong anamnestic response from the patient’s
immune system, leading to continued cancer progression and death from the primary
disease. Several early landmark clinical trials highlighted both the potential of viral
therapy as a cancer treatment, as well as its dreadful side effects. Following a series of
disappointing clinical trials, interest in oncolytic viruses waned in the 1970-80s until
the development of genetic engineering in the 1990s made it possible to alter viral
genomes. This technological advancement allowed manipulations of the viral genome
to improve selectivity and decrease toxicity.
Since then, the development of viral therapy from laboratory to bedside has finally
been realized. ONYX-015 became the first virus to enter Phase I clinical trials in 1996
and the adenovirus mutant H101 became the world’s first OV approved for cancer
treatment in 2005 in China. Following a Phase III trial showing improved durable
response rate for the intralesional treatment of melanoma, IMLYGIC™ (T-
VEC/Talimogene Laherparepvec), a genetically engineered HSV, became the first
oncolytic virus approved by the FDA in October 2015. Thus far, various OVs have
been successfully tested for their oncolytic activities against almost all types of
cancers, and are being evaluated in numerous international Phase I, II, and III clinical
trials.
Figure 2. Brief history of oncolytic virus
How dose oncolytic virus work?
The potential of OVs to improve the therapeutic ratio is derived from their ability to
preferentially infect and replicate in tumor cells while avoiding destruction of normal

3. cells surrounding the tumor (tumor tropism). Two main mechanisms exist through
which these viruses are reported to improve outcomes: direct lysis of tumor cells and
indirect augmentation of host anti-tumor immunity.
Mechanisms of Tumor Tropism
Tumor tropism (selective viral replication in tumor cells but not in healthy tissue) is
important for oncolytic viruses to function as a cancer immunotherapy. Interests in
oncolytic viruses has been increasing based on a better understanding of viral biology,
tumor immunology and molecular genetics. Many viruses have been reported to carry
oncolytic property. As an experienced service provider, we have summarized the
mechanism of oncolytic virus targeting tumor cells.
In terms of oncolytic virus targeting cancer cells, both natural and engineered viruses
take advantage of many differences of genetic characteristics and physiological
features between tumor cells and normal cells, such as activation of proto-oncogene,
the inactivation of tumor suppressor genes, cellular defense mechanism defect,
abnormal growth signals, which result in some differentially or specific expression of
surface receptors, and also exception of signal pathway. Due to the rapid proliferation
of tumor cells, a hypoxic environment formed is another worthy channel. Those
characteristics can make the oncolytic viruses find tumor cells in the complex human
system (Figure 3).
Figure
3. Virus targeting tumor cells in various ways

4. • Cancer cells have been shown to overexpress selected surface receptors, a core
mechanism by which viruses may selectively bind to and infect cancer cells. Measles
virus has been shown to utilize the surface receptor CD46 for cellular entry, which is
overexpressed in a variety of human cancers, including hepatocellular carcinoma,
colorectal cancer, ovarian cancer, and breast cancer.
• Some viruses naturally exploit the aberrant signaling pathways that maintain sustained
cancer growth in order to selectively infect and replicate within cancer cells as
opposed to normal cells. For instance, constitutively active AKT pathway signaling
serves as a sustained growth and survival signal in many different types of cancer.
• In addition, OVs can also capitalize on the hypoxic environment resulting from the
rapid proliferation of tumor cells. The vesicular stomatitis virus (VSV), an oncolytic
RNA virus, is capable of replication under hypoxic conditions. In cells undergoing
hypoxic stress, VSV infection produced larger amounts of mRNA than under normoxic
conditions.
Mechanisms of Action of Viruses Destroying Cancer Cells
Oncolytic immunotherapy employs viruses to directly lyse cancer cells (oncolysis).
These viruses infect tumor cells, where they undergo a series of replication cycles and
are subsequently released through cell lysis to infect adjacent cancer cells. This cycle
can repeat hundreds of times, attacking and decreasing the tumor cell mass. Moreover,
beside this primary effect, OVs can also stimulate the immune system. Tumor is an
immuno-suppressive environment in which the immune system is silenced in order to
avoid the immune response against cancer cells. The delivery of OVs into the tumor
wakes up the immune system so that it can facilitate a strong and durable response
against the tumor itself. (Figure 4)
Figure 4. Mechanisms of actin of oncolytic viruses destroying tumor cells (Omid Hamid,
2017)
Inherent and engineered oncolytic viruses

5. Some viruses demonstrate to be inherently oncotropic to target tumor cells selectively
and more efficiently than normal cells, and trigger the antitumor immune system,
resulting in tumor degeneration and health improvement, such as Newcastle disease
virus (NDV), vesicular stomatitis virus (VSV), parvoviruses, coxsackievirus and
reovirus, which have been directly designed as natural elements in the treatment of
cancer as virotherapy.
Although some viruses exhibit an innate tropism for tumors, other viruses must be
molecularly engineered to selectively infect tumor cells. It is noteworthy that the wide
types of such viruses may carry harmful pathogenic genes, which have to be modified
for deleting. Moreover, the immune response to oncolytic viruses appears to be an
important component of the anti-tumor effect, but it can be a double-edged sword. On
the one hand, viruses can help to promote an immune response against the tumor cells
by allowing tumor antigen presentation in the context of an active viral infection. On
the other hand, neutralizing antiviral responses may block virus replication and
ongoing infection of tumor cells. Therefore, it is also necessary to reduce the antiviral
immune response for unstinted replicating and function.
Advances in molecular biology have afforded the OV field an opportunity to alter the
DNA sequences of viruses and thus engineering viruses that are more specific for
cancer cells than their normal counterparts. In general, viruses are chosen or modified
to selectively target tumor cells, decrease pathogenicity to normal cells, decrease
the antiviral immune response (to prevent viral clearance), and increase the
antitumor immune response. At present, engineering of viruses including
adenoviruses (Ad), Vaccinia viruses, influenza viruses, polioviruses, measles virus
(MV) and HSV has enabled researchers to fight against a variety of cancers.
Based on years of research and timely tracking of information, Creative Biolabs offers
a detailed description about both natural and modified oncolytic viruses, providing you
with a convenient learning platform.
Figure 5. Inherent and engineered oncolytic viruses

6. Prospection
Oncolytic viral therapy has made great strides in recent years. By embracing immune
manipulation as a route to enhanced viral efficacy, oncolytic virotherapy is bound to
rapidly expand in the near future.
As the world's top technology consulting and services platform, Creative Biolabs can
provide comprehensive oncolytic virus therapy development services,
including oncolytic virus construction, oncolytic virus engineering, oncolytic virus
validation, disease-specific oncolytic virotherapy development, which will help you
get satisfactory result in a short time. Creative Biolabs also provides full range of
products to facilitate your researches in the field of virotherapy and gene therapy. Our
service can be designed to meet your special needs if you have any requirements. If
you are interested in our service, please contact us by e-mail and our team will get
back to you as soon as possible.