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CANCER GENE THERAPY
Expression of tumour-suppressor genes:
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Genicidicine and Oncorine function in this manner – the only down sound is that not
all tumours have p53 deficiencies and delivery is not to every single tumour cell,
which means that recurrence is very much a possibility
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There are currently no licensed drugs using this mechanism of action due to the
limited success pre-clinically
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This type of gene therapy targets only cells with specific oncogenes, i
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K-RAS, cmyc, and those that lack these mutations are not affected, and there is no bystander
effect
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Despite the fact that once this vector is delivered the tumour cells can no longer be
ras-independent, there is no clinical benefit because only cells with this particular
mutation will receive the vector and tumours are very heterogeneous
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Furthermore, one tumour cell that has not received this vector can cause tumour
recurrence, and thus increase the chances of secondary mutations due to selective
pressure
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This is a therapeutic strategy, in which cell suicide inducing transgenes are
introduced into cancer cells
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The two major suicide gene therapeutic strategies currently are:
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•
Cytosine deaminase/5-fluorocytosine
HPV/ganciclovir
The replicating murine leukaemia virus (MLV):
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RNA virus with no oncogene and pseudo random integration (when it hits
‘correct’ gene, it becomes oncogenic)
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Reduced immunogenicity of retroviral vectors
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Stable integration, not directly cytolytic and there is the possibility of sustained
presence
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Can provide pro-drug activated cell death by suicide genes
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benefit ratio in poor prognosis maliganancies
Replication competent retrovirus (RCR) vectors for suicide gene therapy:
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This has a better bystander effect than HSVtk/GCV vector
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Multiple cycles of 5-FC can further improve survival, which suggests that there is
a persistence of RCR-CD in metastatic intracranial glioma cells
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Conditionally replicating/oncolytic viruses:
Note: this conditionality is derived from the host
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However, the patient died from malignancy as the immune system attacked the virus
before it could kill all the tumour cells – only one cell is needed for recurrence
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ONYX-015 is deleted in the E1B gene encoding a protein, the major function of
which appears to involve interaction with p53
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- Thus removal of E1A from the adenovirus allows more selective and effective
targeting
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However, it has come to light that this protein may have a number of other roles and
thus tumour selectivity may be oversimplified
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Problem: robust anti-viral immune response causing rapid viral clearance, but
incomplete tumour clearance:
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Problem: inadequate tumour targeting/specificity:
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e
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e
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e
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Conditionally replicating/oncolytic viruses – with enhanced immunogenicity:
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IMMUNE GENE THERAPY – CAR T CELLS:
a
Endogenous T cells express a
single heterodimeric TCR
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c Alternatively, these genes can
encode chimeric tumour
antigen-specific receptors
(CAR) or T bodies, that target
surface antigens in an MHCindependent fashion