Transcript Oncolytic Viruses

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 100000:1. This
therapeutic index is significantly higher than the index
commonly seen in chemotherapy - 6:1- and may result in
greater efficacy with fewer side effects.
Scientific American
October 2003
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.
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.
Morphology and Genomic Organization
of Vesicular Stomatitis Virus
45 -100 nm
Glycoprotein (G)
100 - 430 nm
Nucleocapsid (N)
Matrix (M)
Large Polymerase (L)
Phosphoprotein (P)
Nucleocapsid (N)
Matrix (M)
Phosphoprotein (P)
Glycoprotein (G)
Large (L) Polymerase
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
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.
Normal Cell
IFN
AntiViral
Response
Transformed Cell
IFN
AntiViral
Response
X
The IFN response system is disrupted in transformed cells, thus
permitting selective VSV oncolytic activity, while sparing normal
non-transformed cells.
Eradication of CT26
Lung Metastases
Following Intravenous
or Intranasal
VSV Inoculation
VSV GFP time course in CT26 lung
metastasis
model
12
8 hours
0
11 12
hours
27 hours
24
72 hours
72
5x108 VSV GFP + 5x108 VSV RFP 12hr
VSV in Action: Imaging Oncolysis
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
Oncolytic Viruses in Clinical Trials
Name
Strain
1. Onyx-015 Ad2/5
Alterations
∆E1B-55kD
Mechanism
p53 deficient
Disease
Head/Neck Cancer
Ovarian, Liver
Pancreatic Cancer
Phase
II-III
I-II
I
2. CV706
Ad5
∆E3 Deletion
Oncolysis of PSA Prostate Cancer
E1A-PSA promoter expressing cells
I-II
3. G207
HSV-1
∆ g145.5 deletion
Removal of viral Malignant glioma
counter-attack
I-II
GM-CSF Insertion
Immune
Recruitment
Melanoma
I-II
4. V/GM-CSF VV
5. Reo
Reovirus Naturally
Attenuated
Ras/PKR
Defects
Advanced solid
Tumors
I-II
6. VSV
AV1
IFN
Defects
Advanced solid
Tumors
I
Naturally
Attenuated