Virotherapy for Cancer

1
Virotherapy for Cancer

• Replication-selective Virus,
• or
• Mild, Well-characterized Human Disease,
• or
• Non Virulent Virus

2
Ideal Properties of the Virus

• Non-Integrating
• Genetically Stable
• Non-Replicating in Normal Cells
• Non-Transmissible
• Easy to Grow and Produce

3
Historical Precedents 1920-1950s

• Use of Live Rabies Vaccine in Cancer Patients
• Observation of Spontaneous Remission after a
  Viral Infection
• Attempts with many viruses and many tumors
  temporary regressions only.

4
Recent work (1990?) with Known Mechanisms of
Tumor Selectivity

• Use of Viruses with Inherent Tumor Selectivity
• Deletion of Specific Genes
• Deletion of Genes Necessary for Growth in Normal
  Cells
• Engineering Tumor-Specific Promoters
• Modification of Attachment Proteins (theoretical)

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Viruses with Inherent Tumor Selectivity

• Reovirus
• Vesicular Stomatitis Virus (VSV)
• Newcastle Disease Virus (NDV)
• These viruses grow well in tumors (most) that
  have mutated ras gene, making the cells unable to
  produce interferon.

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Viruses with Inherent Tumor Selectivity
Reo, VSV, NDV all activate
PKR
dsRNA-Activated Protein Kinase Acts in the
interferon response pathway
X
eIF-2
eIF-2
Pi
Protein Synthesis Shut Off Virus cannot replicate
In tumor cells, ras shuts off PKR Thus, Reo and
VSV replicate causing cytolysis
7
Phase I Clinical Trials
No adverse effects observed except mild flu-like
Symptoms compared to controls anti-tumor data
not available.
Previous Studies (1970s-80s)
Use of the viruses (NDV) to infect
patients cancer cells in the lab, followed by
injection of the lysate into the patient.
Immunotherapy Studies were not controlled, but
regression successes have been reported.
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Deletion of Specific Genes

• Herpes Simplex virus
• Gamma 34.5 Neurovirulence Gene
• Virus looses neurovirulence
• Ribonucleotide Reductase (ICP6) Gene
• Can only replicate in growing cells

Used to treat patients with malignant Glioma
brain tumors with no adverse reactions observed
from the virus.
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Deletion of Genes Necessary for Growth in Normal
Cells

• Adenovirus
• Deletion of EIA (Early) 55 kd protein gene
• ..E1A 55kd stimulates cell growth
• ..Cellular growth suppressors pRb, p53 are
  blocked

Cell grows, synthesizes DNA Virus grows, Cell
dies
But without E1A 55 kd, only growing (tumor) cells
support Adenovirus replication and they then die
of viral cytolysis.
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Phase I Clinical Trial Results
Daily injections of virus tolerated
only mild flu-like illnesses. Synergistic (with
Chemotherapy) anti-tumor activity
demonstrated with head and neck tumors, using
intra-tumor injection of the virus. No
activity observed with pancreatic,
colorectal, or ovarian cancers
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Engineering Tumor-Specific promoters

• HSV transcription regulator genes engineered with
  albumin promoter ? Hepatoellular carcinoma cells
  turn the virus on.
• Adenovirus genes engineered with
  alpha-fetoprotein promoter ? targets breast,
  prostrate, hepatocellular carcinomas.

In each case the cellular promoter sequence is
spliced into the viral gene promoter region
yielding a recombinant virus (and safety
concerns).
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Summary

• Several genetically engineered (gene-deleted)
  viruses under investigation.
• Appear to be safe.
• Efficacy not known yet.