Therapy against the tumors

1. ONCOLYTIC VIROTHERAPHY
Dr. Abhishek Kumar Mishra (PhD-AIIMS, New Delhi)
Assistant Professor, Department of Biosciences
Swami Rama Himalayan University
Jolly Grant, Dehradun, Uttarakhand 248140
abhimicro9@gmail.com

2. DEFINITON
Oncolytic virotherapy is a new modality of cancer treatment which
uses competent replicating viruses to destroy cancer cells.
The word Oncolytic Virotherapy means :
 “Onco “ means cancer
 “lytic” means killing
 “viro” means using virus
 “therapy” means for treatment

3. WHAT IS CANCER?
• Cancer is a term used to describe large group of diseases that are
characterized by cellular malfunction.
• Healthy cells are programmed to know “what to do and when to do it”, but
cancerous cells lack this programming and replicate out of control.
• The unregulated cell growth forms a tumor.
• Cancer can result from mutation in either somatic cells or germline cells.
These mutated form of gene is known as oncogenes, which are often
expressed at high levels.
• Traditional oncological approaches, including surgery, radiation, and
chemotherapy, aim to directly remove or kill cancer cells. In contrast,
immunotherapy seeks to enhance the host immune system’s ability to
eliminate cancer cells resulting in tumor regression, antitumor immune
memory formation, and ultimately in durable responses.
• A novel addition to the anticancer treatment armamentarium is use of
oncolytic viruses (OVs).

5. What are oncolytic virus ?
Oncolytic viruses (OV’s) are the viral strains that infect and kill the
cancer cells.
They kill the malignant cells without killing our normal body cells
and also stimulate the body anti tumour immune system responses.
By hijacking the cell's protein synthesis, the virus prevents the cell
from producing host products and promotes the production of viral
products. The infected host cells will lyse and release many sub
viruses that have the ability to infect other cells.
A number of viruses including adenovirus, reovirus, measles, herpes
simplex have been clinically tested as oncolytic agents.
HSV was the first to be used to infect cells as it can be easily
manipulated, and relatively harmless in natural state.

6. Mechanism

7. 1. Inherent oncolytic virus: Some viruses demonstrate to be
inherently oncotrophic to target tumor cells and more effectively
than normal cells. For e.g. Newcastle disease virus (NDV),
Vesicular stomatitis virus (VSV), Parvoviruses etc
2. Engineered oncolytic virus: Some viruses must be molecularly
engineered to selectively infect tumor cells. The wide types of
such viruses may carry harmful pathogenic genes, which have to
be modified for deleting. n 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.
Types

8. ENGINEERED ONCOLYTIC VIRUS
1. Directed evolution:
It involves the creation of new viral variants or serotypes specifically
directed against tumour cells via rounds of directed selection using
large populations of randomly generated recombinant precursor
viruses. The pool of resultant oncolytic viruses can then be further
screened in pre-clinical models to select an oncolytic virus with the
desired therapeutic characteristics.
Directed evolution was applied on human adenovirus, one of many
viruses that are being developed as oncolytic agents, to create a
highly selective and yet potent oncolytic vaccine. As a result of this
process, ColoAd1 (a novel chimeric member of the group B
adenoviruses) was generated.

9. 2. Attenuation :
Attenuation involves deleting viral genes, or gene regions, to eliminate
viral functions that are expendable in tumour cells, but not in normal
cells, thus making the virus safer and more tumour-specific. Cancer
cells and virus-infected cells have similar alterations in their cell
signalling pathways, particularly those that govern progression
through the cell cycle

10. 3. Tumour targeting:
There are two main approaches for generating tumour selectivity:
transductional and non-transductional targeting. Transductional
targeting involves modifying the viral coat proteins to target tumour
cells while reducing entry to non-tumour cells. This approach to
tumour selectivity has mainly focused on adenoviruses and HSV-1,
although it is entirely viable with other viruses.
Non-transductional targeting involves altering the genome of the virus
so it can only replicate in cancer cells, most frequently as part of the
attenuation of the virus.
Transcription targeting can also be used, where critical parts of the viral
genome are placed under the control of a tumour-specific promoter. A
suitable promoter should be active in the tumour but inactive in the
majority of normal tissue, particularly the liver, which is the organ that
is most exposed to blood born viruses. Many such promoters have been
identified and studied for the treatment of a range of cancers.

11. How does Oncolytic virus recognize cancer cells?
The potential use of OV’s as therapeutic agents is derived from their
ability to Infect tumor cells while avoiding destruction of normal
cells, a property known as tumor tropism.

12.  Cancer cells have been shown to overexpress selected surface
receptors, a core mechanism by which viruses may selectively
bind to and infect cancer cells. For eg: Measles virus has been
shown to utilize the surface receptor CD46 for cellular entry,
which is over expressed in a variety of human cancers.
 Some viruses naturally exploit the aberrant signalling pathways
that maintain sustained cancer growth in order to selectively infect
and replicate within cancer cells as opposed to normal cells.
 In addition, OVs can also capitalize on the hypoxic environment
resulting from the rapid proliferation of tumor cells. For eg: The
vesicular stomatitis virus (VSV), an oncolytic RNA virus, is
capable of replication under hypoxic conditions.

14. How does oncolytic virus works?
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.

15. 1. Upon infection with an oncolytic virus, the oncolytic virus repeat
its cycles in tumor cells and causes oncolysis.
2. The release of viral progeny propagates the infection with the
adjacent uninfected cell due to the presence of oncolytic virus and
depletion of immunosupportive cell types such as cancer-associated
fibroblasts (CAFs). Subsequently, dissolved cells release viral
progeny and tumor associated antigens (TAAs) including neo-
antigens, pathogen-associated molecular patterns (PAMPs) and
danger-associated molecular pattern signals (DAMPs).
The TAAs and neo-antigens are released and taken up by antigen
presenting cells (APCs) such as dendritic cells, which participate in
antigen processing and presentation, including increasing major
histocompatibility complex (MHC) class I and MHC class II
expression on APCs, thus increasing the expression of the MHC–
peptide–TCR complex.

17. CURRENT STATUS
The first oncolytic virus to be approved by a national regulatory
agency was genetically unmodified ECHO-7
strain enterovirus RIGVIR, which was approved in Latvia in 2004
for the treatment of skin melanoma.
 The approval was withdrawn in 2019. An oncolytic adenovirus,
a genetically modified adenovirus named H101, was approved in
China in 2005 for the treatment of head and neck cancer.
In 2015, talimogene laherparepvec (OncoVex, T-VEC), an oncolytic
herpes virus which is a modified herpes simplex virus, became the
first oncolytic virus to be approved for use in the U.S. and European
Union, for the treatment of advanced inoperable melanoma.
Recently, ongoing extensive research has suggested that other
viruses like herpes simplex virus (HSV) and measles virus can also
be considered as potential candidates in cancer therapy.

18. ADVANTAGES
Can conditionally replicate within the tumor cells.
Can potentiate to neighbouring tumor cells.
Enhances sensitivity to conventional therapy
Potential to target dispersed tumor cells
Fewer side effects than other treatments.
Cost effective

19. DISADVANTAGES
Immune system can clear virus before therapeutic effects are
elicited
Poor gene transfer efficiency into tumor cells in vivo.
Limit trafficking to brain
Reversal of mutant strain or accidental emergence of new
viral strain
Risk to patients