Oncolytic viruses selectively infect and kill cancer cells. They have a natural tropism for tumors due to differences in tumor and normal cell biology. Oncolytic viruses can kill cancer cells through direct cytotoxicity and immune responses. While early clinical trials in the 1950s saw some tumor regressions but also toxicity, the field of oncolytic virotherapy has advanced significantly with ongoing clinical trials of various virus types. Key areas of research include improving virus delivery to tumors, enhancing intratumoral spread, and stimulating antitumor immunity.

1. Oncolytic Virotherapy
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2. Oncolytic viruses (OVs) are therapeutically useful viruses which selectively infect and
damage cancerous tissues without causing harm to normal tissues. Every virus has a
specific cellular tropism that determines which tissues are preferentially infected,
and what disease is caused. A number of naturally occurring viruses have a
preferential, although non-exclusive, tropism for tumors and tumor cells. This
probably has more to do with tumor biology than with virus biology as most tumors
have evolved not only to avoid immune detection and destruction but also to resist
apoptosis and translational suppression, which are the crucial responses used by
normal cells to limit a virus infection. OVs can kill infected cancer cells in a number of
different ways, ranging from direct virus-mediated cytotoxicity through various
cytotoxic immune effector mechanisms.
Brief Introduction

3. Oncolytic Virus Service
Enhancing intratumoral
spread of OVs
Content
Oncolytic Virotherapy - Sharpening the Sword for Improved Cancer Treatment Strategies
Delivering OVs to
the tumor
Clinical developmentCell-death mechanisms

4. Cell-death mechanisms: immunogenic cell death is important for cancer therapy
OV-mediated cell death does not fit exactly into one of the three classical categories of cell death (apoptosis,
autophagy and necrosis), and likewise cell-death pathways induced by chemotherapy can vary from agent to agent.
Apoptosis is important for development and the maintenance of tissue homeostasis, and is usually considered to be a
nonimmunogenic form of cell death, while necrosis, which is less coordinated and results in the release of
proinflammatory cytokines, has been regarded as immunogenic. Nevertheless, it is now clear that the boundaries
between each classical cell-death pathway are not defined and there is often overlap. This has been demonstrated
through the discovery of “immunogenic” apoptosis in tumor cells, which can be induced by specific chemotherapies,
such as the anthracyclines and oxaliplatin.

5. Cell-death mechanisms: immunogenic cell death is important for cancer therapy
Likewise, OV-mediated cell death does not fit into either
necrosis or apoptosis, but displays features of both, with
variations between oncolytic viral types. Generally, the
immunogenic death of cancer cells involves a multistep process,
beginning with the recognition of pathogen-associated
molecular components, such as viral components, which cause
such molecules as nucleotides, fractalkine, and ATP to be
released, which in turn attract phagocytes or dendritic cells
(DCs), and the expression of such signals as phosphatidylserine
and calreticulin which aid recognition by phagocytes or DCs.
Eventually, danger-associated molecular patterns (DAMPs),
such as HMGB1, are expressed. This enables dying tumor cells
to lose the ability to induce tolerance and stimulate powerful
anticancer immune responses.

6. Clinical development
The idea of using viruses to treat cancer first began to
take hold in the 1950s, when tissue culture systems and
rodent cancer models were originally developed.
Hundreds of cancer patients were treated with impure
oncolytic virus preparations administered by almost
every imaginable route. The viruses were usually arrested
by the immune system and did not affect tumor growth,
but sometimes infection took hold and tumors regressed,
especially in immunosuppressed patients, although they
frequently became sick or died when the infection spread
to normal tissues. Since that first application of virus
engineering to an oncolytic HSV, the pace of clinical
activities has accelerated considerably, with a number of
ongoing or completed trials using OVs belonging to at
least ten different virus families and a steady stream of
new OVs entering the clinical arena.

7. Delivering OVs to the tumor
Although several ongoing trials are emphasizing intratumoral delivery, systemic delivery will be required for treatment of
metastatic cancer. The goal of systemic therapy is to exceed the ‘viremic threshold’ above which the virus nucleates a
critical number of intratumoral infectious centers whose expansion and coalescence lead to tumor destruction.
Therefore, current research is focused on minimizing oncolytic virus sequestration in the spleen and liver, evading
neutralization by serum factors, targeting viruses to the vascular endothelial cells lining tumor blood vessels and
selectively enhancing vessel permeability.

8. Enhancing intratumoral spread of OVs
Mammalian cells have evolved to resist
virus infections. A typical infection
involves attacks on cellular defenses by
viral gene products (virulence proteins),
defensive parries by the host cell
through the elaboration of antiviral
proteins and further counterattacks by
the virus. Viral virulence genes encode
proteins which suppress host defense
systems, facilitate virus spread
between cells and usurp cell metabolic
processes. OVs are selected or
engineered to be attenuated in normal
tissues, often by mutation or deletion
of virus virulence genes.

9. 01 Promoting viral growth by genetic arming and chemical sensitizers;
02 Improving virus spread in tumors;
03 Engineering tumor selectivity into oncolytic virus backbones;
04 Controlling adaptive immunity and clearance of OVs;
05 Enhancing antitumor immunity.
Enhancing intratumoral spread of OVs
Therefore, an oncolytic virus entering a normal cell triggers the cellular antiviral response but cannot
counterattack, so the infection is quickly eliminated. The antiviral response involves production of
proteins that counteract the virus through acting directly against the virus, communicating with
adjacent cells or jump-starting apoptotic programs. There are several approaches to enhancing
intratumoral spread of OVs, including:

10. Oncolytic Virus Service
With years of experience in research of oncolytic viruses as well as our QVirusTM platform, Creative
Biogene expeditiously moves your oncolytic program forward for initial early-stage clinical
evaluation. Creative Biogene provides a broad range of oncolytic virus engineering scope including
herpes simplex virus, adenovirus, measles virus, vaccinia virus, vescilar stomatitis virus, and so on.

11. Oncolytic Virus Service
01
Oncolytic virus
construction
03
Oncolytic virus
validation
04
Disease-specific oncolytic
virotherapy development
02
Oncolytic virus
engineering
We provide customized, reliable and high-quality oncolytic virus therapy development services ranging from
virus engineering, cell assays to animal testing. Various types of oncolytic viruses engineering systems have
been established standardly to facilitate oncolytic virus development with less time and reduced budget.
GMP-compliant manufacture of oncolytic virus is also included in our services.

12. THANKS!
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