Kanjarpane 1

Arjun Kanjarpane
Ms. Mary Jane Sasser
Dr. Sangeetha Underwood
Dr. Samuel Rabkin
Oncolytic Virotherapuetics
IR-3/09GT
2.28.18

Perfecting the Weapon: Novel Approaches to Combat Antiviral Responses and Optimize

Oncolytic Viral Efficacy.

In the intense battle against cancer, the second leading cause of death in the United States

(FastStats), a novel weapon has emerged that shows tremendous promise- viral oncotherapeutics.

All foreign organic molecules face severe immune resistance and molecular biology advances

have enabled the development of viral oncotherapeutics and contain the keys for mitigating

antiviral responses for treatment optimization. Three specific anti-immune response processes

are cellular autophagy, drug-modulated immunosuppression, and increased tumor translation.

While research has shown promise in each of these methods, therapeutic efficacy may be best

optimized by incorporating multimodal approaches.

Viral oncotherapies target cancers, an organic group of diseases in which uncontrolled

cell division takes place, creating masses that have direct and indirect effects on the body

(Cancer). Specific genes called oncogenes lead to cancer formation (Cooper). These are

mutations of genes which normally help cells grow. Mutant oncogenes can stay on beyond

normal conditions and promote cellular replication beyond safe limits and ultimately cause tumor

masses. These organic masses range in size and can be found virtually anywhere in the human

body. The absence of self-programmed cell death or apoptosis gives way to unmodulated cell

division. Direct effects of cancers include limiting blood supply to healthy tissues, diverting
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nutrition, and placing pressure on surrounding tissues to include nerves, vessels, and bones.

Indirect effects include immune and hormonal actions, and corresponding adverse consequences

such as infection, which serve to weaken the human organism further. The collective, cumulative

adverse effects of cancer, promoted by environmental as well as endogenous factors, affecting all

ages, serve to weaken and ultimately cause the body to die. Cancer affects all populations, and

since historical times, the fight to find cures has been a never-ending battle.

There are 1.7 million cases and six hundred thousand deaths in the United States alone

due to cancer (Siegel et al). Cancer affects various body parts, and fatality rates vary based on

multiple factors that include underlying immunocompetency, environmental factors, preexisting

morbidity, and genetic factors. Benign cancers cause little morbidity whereas malignant types

result in high mortality and morbidity (Brain). Although the frequency of malignant cancers is

decreasing in the United States, some types remain resistant to usual treatments. On an annual

basis, 26,000 individuals are diagnosed with glioblastoma, a severe and almost uniformly fatal

brain cancer. This cancer’s significantly high mortality and low cure rates have prompted

researchers to seek more efficacious treatments (Brain).

Since the emergence of cancer in the 15th century, cancer treatments have been

improving. Early treatments were restricted to surgery. Treatments progressed by the turn of the

19th century to chemotherapy, a targeted set of drugs that kill all fast-dividing cells including

tumor, as well as normal cells such as hair, and nail cells as well as beneficial enteric bacteria

(Sudhakar). Side effects of chemotherapeutics were significant (DeVita, Chu). It was seen that

certain cancers such as glioblastoma were resistant to even the highest doses of chemotherapy

(DeVita, Chu). X-rays were discovered in the late 1800s, and in the early 20th Century,
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researchers discovered that radiation therapy improved cancer treatment efficacy (Papac 291).

Multimodal cancer treatment using chemotherapy and radiation, both internal and external, were

the mainstays of medical response in the 1920’s and 1930’s (Papac 291). The serious side effects

of chemotherapy led researchers to study other options for cancer treatment. Immunotherapy

emerged in the 1990s and used elements of the body’s immune system to fight cancer.

Knowledge regarding the existence of the body's “fighting cells,” was well known. How exactly

they worked, and how they communicated with each other and were affected by pathogens, and

tumor cells were and are the core work of molecular biology. Deploying some of the body’s

defenses as treatments, resulting in organic, lab-made molecules, “...including interferons,

interleukins, cytokines, endogenous angioinhibitors and antigens, ...” to kill cancer cells

(Sudhaker). The advances in immunology are expanding into the future with other molecular

biological processes and tools being deployed to overcome cancerous tissues. Gene therapy, or

the alteration of genes to minimize the frequency of unmodulated and rogue oncogenes, has

shown significant clinical promise. Genetically engineering the body’s fighting cells, such as

unmodulated T-cell therapy, has also shown considerable promise (Kelly & Russell). Recently,

molecular biology has advanced to include natural biologic weaponry outside the human body,

such as viruses, and these have shown great efficacy. With molecular adaptations to and

attenuation for potency, viruses have quickly overtaken the forefront of cancer research.

Oncolytic viruses are strains of viruses attenuated for potency and whose genetic

structures are modified to infect only tumor cells and ignore healthy cells (Fukuhara et al). Many

oncolytic viruses exist, but the measles, polio, herpes simplex, West Nile, and adenoviruses

dominate the treatment fields (Kelly & Russell ). These viruses each have specific benefits, and
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each includes specific properties, making them more effective towards certain cancers. The most

malignant types of cancers, breast, lung, and melanoma, are all being treated with oncolytic

viratherapeutics (OV), with better than expected outcomes (Sudhakar). Other cancers being

treated with OV include prostate, colorectal, cervical, brain, and neuroendocrine cancers. Viral

oncotherapeutics are currently being optimized to be the most potent weapon against cancer

cells. This can take place by priming the immune system after virtual induction and post-viral

oncolysis to further destroy cancer cells, or by extending viral survival to increase viral

replication and therefore enhance oncolysis. As discussed, OV is amenable to optimization

through several molecular biology processes, to include cellular mitophagy, drug-modulated

immunosuppression, and increased tumor translation.

The first process to be considered is mitophagy, which is a selective form of autophagy,

which in turn, is a homeostatic process used to remove damaged organelles and foreign bodies.

This process relies on the fusion between autophagosomes which target and store components

for termination, and lysosomes which terminate the cargo held in the vesicles (Ding & Yin).

Mitophagy is mitochondrion-specific autophagy and normally removes damaged mitochondria to

maintain proper cell function and terminate cells. Induction of mitophagy involves two steps:

“induction of general autophagy and priming of damaged mitochondria for selective autophagic

recognition.” (Ding & Yin). Autophagy is both used by the immune system as an antiviral

mechanism and can also be induced by viruses to lyse infected cells and mitigate immune

response (Xia et al).

Oncolytic viruses induce autophagy and mitophagy, and to test this theory, researchers in

one study used intra-virus autophagic stimulants: ATG7, BECN1, SQSTM1 or RAB7. These
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proteins are crucial to pre-autophagosomal formation in mammals. The impairment of these

critical proteins “decreased cell death induced by MV-Edm” (Xia et al). Conversely, the

overexpression of ATG5 or ATG7 enhances virus-induced autophagy which then lyses cells.

When intra-virus autophagic stimulants: ATG7, BECN1, SQSTM1 or RAB7 were impaired

through RNAi mediation, cytokine (virus-replication blockers) production increased, and viral

replication decreased. This led researchers to conclude that autophagic reactions mitigate

immune resistance (Xia et al).

Lung cancer cells in two variants, the AF49 and H1299 cells were observed with and

without MV-Edmonston infection. The autophagosome moved towards cells with the

EGFP-MAP1LC3B transgene. The result number of vesicles increased, evidenced by the GFP

being embedded into the transgene, displaying that the overall lysis of the lung cancer cells.

Cells containing EGFP-MAP1LC3B were subject to MV-EDM infection, at 0.5 viral titer and

cultured for 4h. Following this culturation, cells were stained for MV H protein, to highlight the

protein. After 6 hours, increases in viral titer nor a increase in MV H protein were present and

EGFP-MAP1LC3B levels and quantities remained constant. 24 hours after virus infusion, MV H

protein levels rose astronomically along with a subliminal decrease in EGFP-MAP1LC3B levels.

The 9th square merged these factors and provided evidence to a strong viral titer decrease. This

contributed to the overall understanding that autophagy and the late stage, autophagic flux is

induced in greater quantities after viral infection, and this is specific to the Measles Virus-EDM.

Autophagic stimulants, in this study were added via extra tumoral infusion via injection (Xia et

al). In the future, these types of injections are subject to mutation and will complicate the tumor

microenvironment. To operate more seamlessly, MV-EDM should feature RNA coding for
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inherent autophagic stimulants as part of the viral genome. This process now allows the virus to

replicate and while translating, the virus automatically makes autophagic stimulants. However,

autophagy may be of more benefit when stimulated even further through translation.

Viral titer or concentration is another measurement that can be used to explore the

presence and use of autophagy against viral replication and survival time, and therefore assess

efficacy. Downregulation of the BECN1 and ATG7 and RAB7 was associated with a decrease in

viral titer. This observation signifies that not only does autophagy play a part in the replication

abilities of the MV-EDM virus, but this also describes how late and early stages of autophagy

can contribute to the replication effect. Expression levels of antiviral cytokines rose, “35- and

65-fold” when ATG7 was reduced. Correspondingly, over-regulation of the ATG7 protein

greatly decreased expression of cytokines, OAS1, IFNB1 and IFI27 (Xia et al).

The second process to be considered in OV optimization is immunosuppression, defined

as the process of limiting or disabling one or more of the body’s natural defense mechanisms

(Hartono). Immunosuppression first emerged in the 1930s following the need for a modality to

prolong and postpone foreign organ rejection from the host body. The use of immunosuppression

has been implemented in two ways, using T-cell checkpoint blockers or through drug regimens

which delay the activation of the T&B proteins.

The use of immunosuppressive environments to prolong viral survival is a simple matter

of preventing a limiting factor using well-known and well-explored technologies. From the start

of a viral infection, the human immune system processes traces of viral matter and through

signaling proteins, summons the body’s fighting cells: T & B cells as well as natural killers.
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Immunosuppressive drugs can block this defense and ultimately limit (to varying degrees) an

antiviral response (Hartono et al).

Another immunosuppression modality employs immune checkpoints. These are proteins

that modulate the release of T and B cells after the arrival of signaling proteins. This modulation,

especially downregulation of these proteins, can either delay or advance the initiation of T and B

cell activity. T cells are activated upon the presentation of antigenic peptides which engage with

the T cell antigen receptor. Co-stimulatory T cell receptors, CD28 with associated ligands, CD80

and CD86, are also required for T cell deployment. For example, the immunosuppressant

CTLA-4 works by outmatching CD28 in binding to the associated ligands. The use of CTLA-4

also can delay the time between T cell proliferation and cytokine production (Jacobson).The

downregulation of T cell activation and the delay in T and B cell response can prolong viral

survival be allowing for further replication. Viruses are attacked by the body’s immune response

using the bodies’ ‘fighter’ cells. These T and B cells attack the virus and eventually destroy viral

particles using vesicle-lysosome fusion (Engeland et al). Viral replication increased when the

CTLA-4 protein was used in combination with oncolytic adenovirus. Viral titer increased

profoundly compared to the control model (immunocompetent), the first level of the independent

variable (immunocompetent + adenovirus) and the last level (immunosuppressive + adenovirus)

(Thomas et al).

“Immunosuppression Enhances Oncolytic Adenovirus Replication and Antitumor

Efficacy in the Syrian Hamster Model”, presents the advantage that immunosuppressant drugs

can have on the overall therapeutic efficacy of an oncolytic virus, as measured with tumor

volume. The effect of cyclophosphamide (CP) on the oncolytic efficacy of oncolytic

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adenoviruses VX-007 and AD5 were measured with the immunosuppressive and alone (without)

on hamster adenocarcinoma models. The experiment was measured over the course of five

weeks post-administration of CP and oncolytic adenoviruses against adenocarcinomas. The

independent variable of the study observed the activity of the tumor alone (vehicle), CP alone,

the viruses alone, and the viruses with CP in a tumor microenvironment. The gross tumor

volume (µl), with the vehicle alone at the end of 40 days measured volumes upward of 5,200μl

but did not see any signs of decreased volume. The CP alone did not have a statistically

significant effect on the growth of the tumor and is evidenced by the similar pattern it takes when

growing over the course of 40 days. The overall volume decreased very slightly, about 50μl

compared to the vehicle alone, but this is still statistically insignificant. The infusion of the

oncolytic viruses VRX-OO7 (an adenovirus with an overexpression of the Ad death protein) and

AD5 (an un-attenuated adenovirus serotype) into the environment without CP yielded

satisfactory results with both viruses reaching 2000μl from a previous 8,000μl 40 days post

infection (from a starting 1000μl at day 0). This was significant oncolysis as compared to the

vehicle, but growth was further reduced after CP was added, with tumor volume reaching below

1000μl 40 days post infection with the wild Ad5 virus being slightly more efficacious as it

reached 970μl compared to VX-007, which reached 1,000μl.. With the vehicle alone, with a

7,000μl volume, the oncolytic viruses brought the overall tumor volume lower than the starting

point, and lower than the viruses alone, proving the modality as beneficial to overall therapeutic

efficacy. Specifically, the first two weeks saw both immunosuppressant and immunocompetent

environments display no noticeable differences but researchers report that immunocompetent

hamsters began to display tumor regrowth, which is represented on the first graph by the incline
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in tumor volume around day 14 and 15. The overall conclusion represents the ability for

immunocompetent environments to host viruses for longer periods of time leading to longer

oncolysis and in turn, a prolonged period of cancer remission.

Studies have shown that checkpoint inhibition results in more tumor lysis. Murine

models are commonly used as subjects for in vivo experiments due to their many similarities

with human models. Murine models with inserted B16 cells (since CD46 lacks in mouse models)

displayed that oncolytic viruses with modified checkpoint blockades (CTLA-4) were able to lyse

more cells and have greater viral titer than a non-modified virus. This observation allows for

great evidence pointing to the use of immunosuppressive abilities in virus environments

(Engeland et al).

Abrogating immune response is crucial to overcoming one of the major limitations to

oncolytic virotherapy. Though discussed previously, oncolytic virus-induced autophagy deserves

an additional emphasis due to its ability to tilt the fight against the immune system in the viruses’

favor. This, in turn, creates greater therapeutic efficacy (Gang et al). Cellular mitophagy, in

conclusion, uses a viruses’ natural ability to limit antiviral response and downregulate cytokine

synthesis while using this to the virus’s benefit. Greater replication can allow the virus to reach,

infect and lyse more tumor cells and achieve greater therapeutic efficacy. The overexpression of

mitophagy and autophagy-inducing stimulants can provide benefits in viral survival, and these

modalities can serve as crucial virus-based factors which can abrogate immune response.
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The importance of using a well-studied approach to achieve increased efficacy is

important, as medical treatment in this field ultimately involves humans. Immunosuppressive

technologies have existed since the first organ transplants and have worked for most patient

populations (Hartono et al). As in all in vivo experiments, multiple events affect the outcome of a

given modulating factor. Interventions whose outcomes and interactions are measured can allow

for greater confidence in clinical trials and eventually, lead to a full-fledged treatment option.

A third modality to enhance OV efficacy is through increased tumor translation.

Translation is a molecular biology process wherein a messenger RNA (mRNA) sequence is

understood and translated into amino acids, which eventually form proteins (Molecular).

Translation is a step in protein synthesis where genetic material is carried by mRNA and is

decoded to produce amino acids needed to create polypeptide chains and eventually proteins.

This process occurs in the ribosome and is present in all cells. This translation process also

occurs in tumor cells. Novel molecular biology solutions allow for the modulation of this process

to either slow or expedite the protein synthesis process.

Modulating tumor translation affects the speed at which it can divide and make more

cells. Translational control of the virus dictates the rate at which new proteins are produced and

thus the rate at which new cells are produced. Viral replication throughout the tumor intensifies

as the tumor itself multiplies at a faster rate. Transitional control of the tumor tissue also allows

for the programmed safety mechanism to protect healthy cells from unexpected viral replication:

if the virus spreads at an unexpectedly high accelerated rate, the “translational inhibition

(modification) suppresses measles virus potency.” In another study, using IGF-I stimulation of

mesothelioma cells activated the eIf4F complex which, “thereby triggers cap-dependent
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translation,” and, “stimulation of host [tumor] cell translation…,” and this resulted in enhanced

measles activity which therefore increases strength and potency toward tumor cells and immune

cells alike. The assessment of the impact that this stimulation had on MV activity was

symbolized by cell viability which, 24 hours later was “significantly reduced” in IFG-I models

treated with MV than in non-transitionally stimulated MV-infected models (Jacobson et al). The

increased potency of the virus because of stimulated transitional control describes how

transitional control can be modulated to fit the viruses needs.

Virus infusion and control relies heavily on translatory measures, as by itself, viruses are

not a stable platform to induce protein synthesis needed for viral survival and transmission.

Measuring the effect of transitional control in a tumor of viral control measures the rate at which

proteins are produced within the tumor, and inferentially the virus. This rate, is increased,

increases both the rate of tumor multiplication and virus multiple. To measure the effect of

translational control on virus survivability and overall efficacy, a translational inhibitor called

eIF4E targeted antisense oligonucleotide (ASO) was used to treat H514, H2461, H2596

mesothelioma cancer cells with MV-CEA, a measles virus which over expresses the

carcinoembryonic antigen. A mismatch control ASO was used for control purposes. 48 hours

later, cell viability in H256 cells decreased from 1.1 to 0.5, more than 200% reduction. Levels of

CEA were present in all cells inside the tumor environment, however cells infected by MV-CEA

and not mmAS, 4EASO displayed 300ng/ml of CEA compared to the other two CEA acquiring

methods in H513 cells, while the CEA levels in H2373 cells was closer to 200 in MV-CEA cells.

These results display that the mismatch control item had an inhibitory effect upon the H513 cell

line. 75% of cells tested displayed unviability while 25% displayed continued viability with
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continued use of the MV-CEA virus as well as 3EASO. Transitional stimulants such as IGF-I,

after 24 hours in use with MV-CEA drastically lowered CEA levels, reaching a staggering 60

ng/ml of CEA in cells.

When using biological weapons such as viruses, that have tendencies to mutate or

genetically reshuffle, safety systems including ones to drastically limit virus potency are vital.

For example, the backward compatibility of transitional suppressants (as compared to transitional

stimulants) that can to test the effect of 4E-BP1A37/A46 to suppress measles virus (MV)

activity. In testing, multiple melanoma cells were treated with MV-GFP, along with this

suppressant, and this resulted in less cytotoxicity. On the contrary, the transitional stimulant

IGF-1 added MV efficacy (Jacobson et al).

Overall, the ability to have controlling factors outside of virus-modulatory items allows

for direct control of the strength of the MV-virus. This can allow for greater control of viral

efficacy for safety-related and other strategic objectives. The proven effects of translational

stimulants and their effects on viral strength and titer are therapeutic hallmarks in the cancer

treatment pathway. Likewise, translational control is proven to be valid modality to control

antiviral response. Due to its novel approach to limiting viral strength through tumor

reproduction, blunting antiviral efficacy through increased viral titer secondary to translational

tumor control deserves further research.

Prior treatments for malignant tumors have existed from the early 18th century. While the

earliest treatments included surgery to remove cancerous material, these treatments had low

success rates due to serious complications to include infection. Chemotherapy has worked for
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many, but the resulting side effects and concomitant treatment failures continue to suggest that

more optimal treatments should be researched. The use of novel treatments, to include biologic

agents such as viruses and the body’s immune system, holds promise that a more synchronous

and efficacious treatment is possible for cancer.

The importance of using biological agents of disease to face an ever-changing malignant

enemy is supported by the continual stream of innovations in molecular biology (Harris

6097-6101). Furthermore, the level of modularity, eons of viral development and adaptation,

suggest that viruses are a perfect therapeutic candidate for tumor elimination (Vile). Historical

and recent evidence supports the fact that viruses have the molecular development to be the

perfect tool to replicate, infect and destroy cells. Furthermore, virology research to include

modulation, modification, and adaptability is strong, as is work into associated viral processes.

The use of multimodal approaches to combat various issues in medicine is vast. Multiple

antibiotics treat tuberculosis, and the combination of surgery, chemotherapy, radiation for cancer

is also very effective.. Viral-oncotherapy has also seen multimodal approaches in using the virus

to first, directly lyse tumor cells and then initiate a subsequent major immune response to destroy

enhanced numbers of tumor cells. The use of unmodulated T cell blockade research enhances

this therapeutic approach (Vile). However, there is limited research into the deployment of

multimodal approaches to combat antiviral immune responses. Further research into the effect

had by combining approaches should yield answers that help optimize therapeutic efficacy and

attenuate their respective shortcomings.

The human body initiates severe and efficacious responses to combat foreign attacks.

Many of these attacks attempt to destroy foreign bodies such as bacteria or viruses. To place a
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virus in an environment fraught with survival challenges, certain modifications must be used to

help aid viral survival, and therefore, subsequent oncolytic rate and efficacy. Combining

modalities to help double or triple individual efficacy, holds promise in the innovative field of

viral oncotherapeutics.
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Appendix A, Definitions:

Oncolytic Virus: A genetically modified virus which is attenuated for potency and is used to kill

cancer cells while keeping healthy cells alive.

Autophagy: A homeostatic process in which autophagosomes fuse with lysosomes to degrade

organelles for reuse.

CTLA-4: A immunosuppressant drug used frequently to suppress the immune system to allow

for foreign substance intrusion.

Tumor Translation: The process of the nucleus decoded chromosomes and then produced

messenger RNA (mRNA) to produce new cells.

Efficacy: The rate at which something does its job.

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Appendix B: Data

Cellular Mitophagy

Translation
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Immunosuppresion
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