Oncolytic Viruses

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Oncolytic Viruses
Onco cancer Lytic killing
An innovative cancer therapy that seeks to
harness the natural properties of viruses to aid
in the fight against cancer. These non-human
viruses replicate in cancer cells and leave
normal cells largely unaffected. Clinical data
indicates that oncolytic viruses have a very high
therapeutic index, in some instances 1000001.
This therapeutic index is significantly higher
than the index commonly seen in chemotherapy -
61- and may result in greater efficacy with
fewer side effects.
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Scientific American October 2003
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A Historical Perspective on Therapeutic Viruses
Early human trials using viruses in anti-cancer
treatments initially yielded excitement as tumor
regression was often seen without toxicity
however, tumor regression was followed by tumor
progression during the late stages of these
trials.
As a result of these early clinical trials, the
idea of using viral vectors diminished in the
hopes that a better understanding of cancer
biology would allow for the development of more
effective approaches.
Recently there has been a renewed interest and
optimism in virotherapy with the convergence of
ideas from molecular oncology and virology, and
the development of recombinant virus
technologies.
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Vesicular Stomatitis Virus
VSV is not a human pathogen and thus the host
lacks neutralizing antibody against the virus.
VSV generally causes mild, non-fatal disease in
cattle and swine. The inability of VSV to
cause mortality in animals or humans is a result
of its sensitivity to the host antiviral response
- a response that appears defective in
cancer cells. VSV is an attractive candidate as
a viral delivery system for a variety of reasons
1. VSV is easily manipulated by recombinant
techniques. 2. VSV can be grown to very high
titers (1010 pfu/ml) 3. VSV is non-pathogenic in
humans.
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Morphology and Genomic Organization of Vesicular
Stomatitis Virus
Nucleocapsid (N)
Matrix (M)
Phosphoprotein (P)
Glycoprotein (G)
Large (L) Polymerase
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VSV Oncolytic Activity Targets Many Different
Tumor Types

• Breast tumour-derived cells and tissue

• Ovarian carcinoma

• Prostate cancer

• Melanoma

• Colon carcinoma

• Lung tumour-derived cells and tissues

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Why is VSV Oncolytic?
Although it has been known for some time that VSV
selectively infects and kills transformed cells,
the mechanism has remained unknown.
The IFN response system is disrupted in
transformed cells, thus permitting selective VSV
oncolytic activity, while sparing normal
non-transformed cells.
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Eradication of CT26 Lung Metastases Following
Intravenous or Intranasal VSV Inoculation
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VSV GFP time course in CT26 lung metastasis
model
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8 hours
11 hours
27 hours
72 hours
0
24
12
72
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5x108 VSV GFP 5x108 VSV RFP 12hr
VSV in Action Imaging Oncolysis
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Conclusions
VSV is an excellent candidate oncolytic virus
with a broad range of anti tumor effects
Attenuated VSV strains with mutations in the
viral matrix protein fail to block the
development of innate immunity and provide a
better therapeutic virus
Curing cancer in mice is easy .. the challenge
is to determine the efficacy of several
different oncolytic viruses in a variety of
human tumors
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Oncolytic Viruses in Clinical Trials
Name Strain Alterations
Mechanism Disease
Phase 1. Onyx-015 Ad2/5 ?E1B-55kD
p53 deficient Head/Neck Cancer
II-III

Ovarian, Liver I-II
Pancreatic Cancer I 2. CV706
Ad5 ?E3 Deletion Oncolysis of
PSA Prostate Cancer I-II
E1A-PSA promoter
expressing cells 3. G207 HSV-1 ?
g145.5 deletion Removal of viral
Malignant glioma I-II
counter-attack 4. V/GM-CSF VV
GM-CSF Insertion Immune Melanoma
I-II Recruitment 5.
Reo Reovirus Naturally
Ras/PKR Advanced solid
I-II Attenuated Defects
Tumors 6. VSV AV1
Naturally IFN Advanced solid
I Attenuated Defects
Tumors