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ONCOLYTIC VIRUSES AS ANTICANCER
AGENTS
BY
ADEOYE OPEYEMI ADURAGBEMI
OUTLINE
ü INTRODUCTION
ü HISTORICAL BACKGROUND
ü ONCOLYTIC VIRUSES AS AN ANTICANCER AGENT
ü GENOMIC ORGANISATION OF SOME SELECTED ONCOLYTIC VIRUS
ü MECHANISMS OFANTITUMORAL EFFICACY OF ONCOLYTIC VIRUSES
ü TUMOR SELECTIVITY/SPECIFICITY
ü ONCOLYTIC VIRUSES AND THEIR GENETIC MANIPULATIONS IN CLINICAL
TRIALS
ü ADVANTAGES AND DISADVANTAGES OF ONCOLYTIC VIRUSES
ü BENEFITS AND LIMITATIONS OF GENETIC MANIPULATION WITH POTENTIAL
SOLUTIONS
ü FUTURE PROSPECT OF ONCOLYTIC VIRUSES
ü CONCLUSION AND RECOMMENDATION
ü REFERENCES
INTRODUCTION
v Cancer continues to be a leading cause of death, accounting for 8.2 million
deaths worldwide in 2012.
v Cancer mortality with incidence projected to rise from an estimated 12
million cases in 2012 to 22 million within the next twenty years (Bradley et
al., 2014 ).
v Recently according to the WHO, over 100,000 Nigerians are diagnosed with
cancer annually and about 80,000 die from the disease.
v WHO estimated that 240 Nigerians die per day or 10 per hour die from
cancer disease.
v The Nigerian cancer death ratio of 4 in 5 is one of the worst in the whole
world
v Early human trials using viruses in anti-cancer treatments
initially yielded excitement as tumor regression was often
seen without toxicity.
v However, tumor regression was followed by tumor
progression during the late stages of these trials approaches.
v 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.
CONTD…
TABLE 1: CLINICAL VIROTHERAPY: FOUR HISTORICALLY SIGNIFICANT CLINICAL
TRIALS
Abbreviations: IA, intra-arterial; IT, intratumoral; IV, intravenous; TC, tissue culture.
Source:Kelly andRussell,2007.
Year(s) Virus Disease
No. of
patient
s
Administration Outcome Side effect
1949 Hepatitis B virus
Hodgkin's
disease
22
Parenteral injection of
unpurified human
serum, tissue extract
4/22 reduction in tumor
size, 7/22 improved in
clinical aspect of disease;
14/22 developed
hepatitis;
Fever, malaise,
death (1
confirmed)
1952
Egypt 101 virus
(early passage
West Nile)
Advanced,
unresponsive
neoplastic
disease
34
IV, intramuscular
injection of
bacteriologically
sterile mouse brain,
chick embryo, human
tissue
27/34 infected; 14/34
oncotropism; 4/34
(transient) tumor
regression
Fever, malaise;
mild
encephalitis (2
confirmed)
1956
Adenovirus
adenoidal-
pharyngeal-
conjuctival virus
(APC)
Cervical
carcinoma
30
IT, IA, IV injection of
TC supernatant
26/30 inoculations
resulted in localized
necrosis
Vaginal
hemorrhage;
infrequent
(3/30) fever,
malaise
1974
Mumps virus (wild-
type, non-
attenuated)
Terminal cancers;
gastric,
pulmonary,
uterine account
for more than
50%
90
External post-
scarification; IT; IV;
oral; rectal; inhalation
of purified human
saliva or TC
supernatant
37/90 complete
regression or decrease
>50%; 42/90 decrease
<50% or growth
suppression; 11/90
unresponsive
7/90 adverse
reactions:
bleeding, fever
ONCOLYTIC VIRUSES
v Literally, Onco- refers to cancer while Lytic- refers to killing
v Oncolytic viruses (OVs) are viruses that have the ability to
specifically infect and lyse cancer cells, while leaving normal
cells uninfected.
v Examples are
üAdenovirus
üVaccinia virus
üVesicular stomatitis virus (VSV)
üSeneca valley virus (SVV)
üReovirus
üMaraba virus
üNewcastle disease virus (NDV)
CHARACTERISTICS OF IDEAL
ANTICANCER VIRUS
vSpecific in action
vReplicate only in tumor cells
vHighly lytic
vAble to induce anti-tumor immune response
to the host cells.
Figure 1: Generalised diagram of the cancer specificty of oncolytic
viruses (Mode of action)
The diagram above illustrates how oncolytic virus encounter normal cells and cancer
cells.
Source: Wilkipedia online(modified 2015).
Table 2: Mechanisms of antitumoral activity of oncolytic viruses
Mechanism Examples
1.
Direct cell lysis due to viral
replication
Adenovirus ,Herpes simplex
virus
2.
Direct cytotoxicity of viral
proteins
Adenovirus
E4ORF4,E3KPO11.6kD
3.
Induction of antitumoral
immunity
• Nonspecific (e.g., TNF) Adenovirus (E1A)
• Specific (e.g., CTL response) Herpes simplex virus
4.
Sensitization to chemotherapy
and radiation therapy Adenovirus (E1A)
5. Transgene expression
Adenovirus (AdTK-RC)
Herpes simplex virus (rRp450)
Vaccinia virus (GM-CSF)
Source: Kirm, 1996.
GENETIC MANIPULATION OF ONCOLYTIC VIRUSES
v The resistance of cancers to conventional therapies has inspired
the search for novel strategy called gene therapy.
v based on manipulation of viral gene / viruses as genetic vectors.
v These involve use of replication-competent viruses.
v This require understanding genome of the virus to be use(Ring,
2002).
CONTD…
v Knowledge of the pathogenesis of virus diseases and ability to manipulate
specific regions of viral genomes have allowed the construction of viruses
that are attenuated in normal cells but retain their ability to lyse tumor
cells and also will enhance an immune response against it.
v Such manipulations include modifying the ability of the viruses to bind to,
or replicate in a particular cell type while others have involved the
construction of replication-competent viruses encoding suicide proteins or
cytokines (Ring, 2002).
MECHANISMS OF TUMOR SELECTIVITY/SPECIFICITY
There are six general mechanistic approaches to tumor-selective
replication described to date. These include:
(a) The use of viruses with inherent tumor selectivity (e.g., NDV,
reovirus, VSV(Coffey et al., 1998)
(b) Deletion of entire genes e.g. HSV, adenovirus, vaccinia
(Mastrangelo, et al., 2000)
(c) Replacement of functional gene regions e.g. adenovirus,
poliovirus (Gromeier et al., 2000).
CONTD…
(d) Engineering of tumor/tissue–specific promoters e.g.
adenovirus, HSV (Miyatake, et al., 1997)
(e) Modification of the viral coat to target uptake selectively
to tumor cells (e.g., adenovirus, poliovirus)
(f) Insertion of genes such as those encoding suicide
proteins, tumour suppressor proteins or cytokines into
tumour cells by means of a genetic vector.
CRITERIA FOR SELECTING ONCOLYTIC VIRUSES AGAINST
TUMORS
vPathogenesis of the oncolytic virus (biological
behavior of the virus)
vTumor type
vTropism of the virus in relation to location of the
tumor
vPresence of viral receptor in the target tumor cells.
GENOMIC ORGANISATION OF ONCOLYTIC VIRUS
Genomic diversities occur among the oncolytic viruses
v DNA viruses such as Herpes simplex virus-1, Myxoma virus and
vaccinia virus
v RNA viruses such as vaccinia virus, Newcastle disease virus, Seneca
Valley Virus, Reovirus and Maraba virus.
v It is worthy knowing that most of the oncolytic viruses are RNA Virus
because of their small virion size.
Figure 2: Morphology and genomic organisation diagram of Adenovirus.
dsDNA, Adenoviridae,nE
Icosahedral symmentary,
with 20 faces, CAReceptor,
Particle-70-90nm in Diameter
CV706 (PSA),ONYX-015
Source: Banko and Harrach 2003.
Figure 3:GENOMIC ORGANISATION OF MARABA VIRUS AND
VESICULAR STOMATITIS VIRUS
Source: Brun J. et al., 2010
Rhadovirus family
Vesiculovirus genus
-ssRNA, E unsegmented
3’ NPMGL5’
NonPathogenic in human
Sensitive to interfron
3 5
, ,
Figure 4:GENOMIC ORGANISATION OF HERPES SIMPLEX
VIRUS
HSV-neurotropic,DNA,Herpesviridae, nonEssential 30kb-15K,NV1020.
UL56genes (4,6mp of Us),Us12genes, Repeat unit of a-c
Figure 5:GENOMIC ORGANISATION OF VACCINIA VIRUS
Source: Baroudy and Moss, 1982.
Figure 6: Morphology and genomic organisation
diagram of Measles virus.
Source: Rima et al.,2009
-ssRNA, Paramyxo, Morbillivirus
3 gene code for H ,M,F
W.T –CD150
Attenuated MV edm- CD 46
Figure 7:THE GENOMIC STRUCTURE OF POLIOVIRUS
TYPE 1
+ssRNA,nE,PvEnterovirus
7500nucleotide Long
CD155r (PVR),30nm viral Particles
PV1(RIPO).
Source: Goetz and Gromeier, 2010
Poliovirus as an oncolytic agent
v Poliovirus is a natural neuropathogen, making it the obvious choice for
selective replication in tumors derived from neuronal cells.
v Poliovirus replicates in the GIT, the virus invades the central nervous
system (CNS) where it targets predominantly motor neurons, thereby
causing paralysis and even death (poliomyelitis).
v Generally, poliovirus replicates efficiently in nearly all tumor cell lines
tested, which has led to the suggestion that it may be suitable for the
treatment of different cancers.
v However, the possibility that poliovirus can cause poliomyelitis calls for
significant neuro attenuation to avoid collateral neurologic complications
in cancer treatment.
v Poliovirus has a positive -strand RNA genome, the
translation of which depends on a tissue-specific internal
ribosome entry site (IRES) within the 5' untranslated
region of the viral genome, which is active in cells of
neuronal origin and allows translation of the viral
genome without a 5’ cap replaced the normal poliovirus
IRES with a rhinovirus IRES, altering tissue specificity. The
resulting PV1(RIPO) virus was able to selectively destroy
maglinant glioma cells, while leaving normal neuronal
cells untouched (Gromeier et al. 2000)
TABLE 3: SUMMARY OF SOME SELECTED ONCOLYTIC VIRUSES AND THEIR GENETIC
MANIPULATIONS IN CLINICAL TRIALS
Virus Deletions/Mutations Foreign gene/promoter insertion Tumors targeted in
studies
VACCINIA
VIRUS
JX-594
Deletion of both copies of TK
gene
Human GM-CSF and lacZ insertion into
the TK gene region
EWS, lymphoma,
NB, RMS, Wilms
tumor . PhaseI/II
HSV-1
G207
Deletion in both copies of γ134.5
gene and disabling lacZ insertion
in UL39
None Phase II
Glioma, MDB, OST,
RMS, Colorectal
cancer
HSV1716 Deletion in both copies of γ134.5
gene
None Non-CNS solid
tumors
M002 Deletion in both copies of γ134.5
gene
Murine IL-12 gene insert Glioma, RMS
rQNestin34.5 Deletion in γ134.5 gene and UL39 ICP-34.5 under control of a synthetic
nestin promoter
Glioma, NB
rQT3 Deletions in ICP6 and γ134.5
gene
Tissue inhibitor of MMP3, HSV-1
immediate early 4/5 promoter
NB, MPNST
Table continue
HSV-1
VAE
Deletion in both copies
of γ134.5 gene
Endostatin–angiostatin fusion
gene insert
Glioma
Chase-ABC Deletion of both copies of
γ134.5 and in-frame gene-
disrupting insertion of
GFP within the ICP6 gene
Inserted Chase-ABC cDNA under
the viral IE4/5 promoter within
the ICP 6 locus
Glioma
Measles
virus
Engineered to target
CD46 on tumor cells
Phase I
Brain,MM
CNS
tumor
Adenovirus
OBP-301 Deletion of native E1
promoter of Ad5
Human hTERT promoter to drive
E1A and E1B expression linked to
an internal ribosome entry site
Phase III
OST
AD5/3-
Cox2L-D24
Deletion of Rb binding
region from the E1A gene
Inserted cyclooxygenase -2 (COX-
2) promoter
NB
ICOVIR-5 Deletion of Rb binding
region from the E1A gene
Substitution of the E1A
promoter for E2F-responsive
elements, RGD-4C peptide motif
insertion
NB
Table continues
Abbreviation:Ad5, adenovirus serotype 5; CIK-vvDD, cytokine-induced killer double-deleted vaccinia virus; CNS, central nervous system;
EWS, Ewing's sarcoma; GM-CSF, granulocyte colony-stimulating factor; hTERT, human telomerase reverse transcriptase;
IL;interleukin; MDB, medulloblastoma; MMP3, metalloproteinases-3; MPNST; malignant peripheral nerve sheath tumor;
MYXV,-myxoma virus; NB, neuroblastoma; OST, osteosarcoma; RB, retinoblastoma; RGD, arginine-glycine-aspartic acid;
RMS-rhabdomyosarcoma; SVV, Seneca valley virus; TK, thymidine kinase; VSV, vesicular stomatitis virus
Delta-24-RGD Deletion of Rb binding
region from the E1A
gene
Inserted RGD into
the H1 loop of the
fiber protein
Glioma
CRAd-Survivin-
pk7
Deletion of native E1
promoter of Ad5,
polylysine
modification in the
fiber knob
Human survivin
promoter to drive
E1 expression
Glioma
Reovirus type 3
Dearing
None None MDB, RMS, OST,
EWS
Seneca Valley
Virus
SVV-001
None None EWS, glioma, MDB,
NB, rhabdoid tumor,
RB, Wilms tumor.
Phase I
Source: Friedman et al., 2011.
Table 4: Specific Advantages and Disadvantages of different oncolytic viruses
Virus Virus
type
Insertio
n size
Advantage Disadvantages
HSV-1
(152 kb)
DNA 40-50kb Neurotropic
Ability to infect a wide variety of tumors
Large amount of nonessential genes can
be replaced with foreign DNA to enhance
cytotoxicity
Clinically available antiviral agents
Systemic delivery may be
limited by preexisting
immunity and hepatic
adsorption
Adenovirus
(36 kb)
DNA 7.5kb Ability to infect a wide variety of tumors
with modifications of the fiber knob
Large amount of nonessential genes can
be replaced with foreign DNA to enhance
cytotoxicity
CAR variability in human
cancers
Systemic delivery may be
limited by preexisting
immunity, hepatic
adsorption and toxicity.
Small insert capacity
Reovirus RNA ? Wild-type virus causes mild to no disease
Systemic delivery possible
Activated Ras or Ras
effectors necessary
Inability to enhance
infection with foreign DNA
Maraba
virus
RNA ? Ability to boost adaptive antitumor
immunity.
Does not cause human disease
Limited preclinical data.
unknown mechanism of
action
VV
(187 kb)
DNA 25kb Ability to infect a wide variety of tumors
Large amount of nonessential genes can be
replaced with foreign DNA to enhance
cytotoxicity
Inefficient systemic
delivery
NDV RNA ? Targets cancer cells with loss of interferon
responsiveness.
Ability to express foreign DNA to enhance
cytotoxicity
Used safely in children with recurrent
gliomas.
Immune-mediated
clearance of virus.
Transgene insertion reduces
viral replication.
MYXV DNA ? Targets cancer cells with altered Akt signaling
Does not cause human disease
Limited preclinical data in
pediatric cancers
VSV RNA ? Targets cancer cells with loss of interferon
responsiveness
Limited preclinical data in
pediatric cancers
Uncertain tumor selective
oncolytic effect
SVV RNA ? Virus does not cause human disease Mechanism of infection
unclear
Inability to enhance
infection with foreign DNA
Source: Friedman et al., 2011
GENERAL BENEFITS AND LIMITATIONS OF ONCOLYTIC VIRUSES
Benefits
1. Effective tumor removal
2. Limited or no side-effects
3. Selectivity
4. Cost-efficiency
Limitations
1. Revertant of mutant virus (accidental emergence of a new viral pathogen)
2. Deletion of viral genes
3. Anti Immune response of the host.
4. According to Russell, 1994, the limitation to Oncolytic viruses are the safety
concerns arising from the use of it, for human cancer therapy, these can be
divided into two areas:
v Risk to the patient
v Risk to the population (Serious epidemics)
Possible solutions
v Use of a competent replicative virus
v further attenuation of the virus
v Suppressing the host immune response or enabling the virus
to evade immune recognition
v Use non-transmissible virus and preferably derived from a
virus to which the population is generally immune.
v use of an ideal oncolytic virus which should be selective for
the tumor, nonpathogenic for normal host tissues, non-
persistent and genetically stable (Russell, 1994).
PROSPECT OF ONCOLYTIC VIRUSES
v Despite the fact that Oncolytic viruses may be effective
against cancer cells without any supplements; the
combination of chemotherapy or radiation therapy with
oncolytic virus may be highly efficient in cancer destruction.
v Oncolytic viruses can be used as vector for the delivery of
vaccine.
v There is now a compelling need to develop new classes of
anticancer agents with little or no side effect.
Conclusion and Recommendation
v Cancer virotherapy is a rapidly maturing field that will be an integral
part of future cancer therapies.
v With the advent of genetic engineering a wide range of viruses are
being manipulated and evaluated into various types of cancers.
v Many clinical trials around the world have had good results with
high success rates using oncolytic virotherapy, and many more
clinical trials are in progress with new viral vectors for the
treatment of intractable cancers.
v Nigeria should not be left behind! It is thus recommended that our
research centers should be actively involved in clinical trials of
these anticancer agents.
REFERENCE
Baroudy B M, Moss B, (1982). Sequence homologies of diverse length tandem repetitions
near ends of vaccinia virus genome suggest unequal crossing over
Brun J, Dan M,Charles L, Kang H,Theresa F, Harold A, John C , J. Andrea M, Douglas
M,and David F S (2010).Identification of Genetically Modified Maraba Virus as an
Oncolytic Rhabdovirus
Christopher . A.Ring (2002), cytolytic viruses as potential anti-cancer agents
Coffey M, Strong J, Forsyth P, Lee P. Reovirus therapy of tumors with activated ras
pathway Science 1998 282: 1332–1334 | Article | PubMed | ISI | ChemPort
Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E. Intergeneric poliovirus
recombinants for the treatment of malignant glioma [see comments] Proc Natl Acad Sci
USA 2000 97: 6803–6808 | Article | PubMed | ChemPort |
Hales LM,Knowles NJ,reddy PS,Xul, HayC, Hallenback PL,(2008) Complete
genome sequence analysis of Seneca Valley virus-001, a novel oncolytic
picornavirus.
Johnsonston JB, Barrett JW, Nazarian S H, Goodwin M,Ricuito D,Wang
G,Mcfadden G,(2005) A poxvirus-encoded pyrin domain protein interacts with
ASC-1 to inhibit host inflammatory and apoptotic responses to infection
Kim M, et al. 2011. Attenuated reovirus displays oncolysis with reduced host
toxicity. Br. J. Cancer 104:290–299
Mastrangelo M, Eisenlohr L, Gomella L, Lattime E. Poxvirus vectors:
orphaned and underappreciated J Clin Invest 2000 105: 1031–
1034 | PubMed | ISI | ChemPort |
Novelli, A. & Boulanger, P. A. (1991). Deletion analysis of
functional domains in baculovirus-expressed adenovirus type 2
fiber. Virology 185, 365-76
Osada S., Carr B. I. Critical role of extracellular signal-regulated
kinase (ERK) phospholylation in novel vitamin K analog-induced
cell death. Jpn. J. Cancer Res., 91: 1250-1257, 2000
Rima BK AND Duprex W.P (2009).The m easles virus
replication cycle. Curr Top Microbiol Immunology.
Russell S(1994). Replicating vectors for cancer therapy: a question of strategy.
Seminars in cancer biology.5:437–443
Russell,S.(2002). Cancer gene therapy, RNA viruses as virotherapy agents
Rux, J. J. & Burnett, R. M.(2004). Adenovirus structure. hum Gene Ther 15,
1167-76
Stouten, P. F., Sander, C., Ruigrok, R. W. & Cusack, S. (1992). New triple-helical
model for the shaft of the adenovirus fibre. J Mol Biol 226, 1073-84
Strong J. E., Coffey M. C., Tang D., Sabinin P., Lee P. W. K. The molecular basis
of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO
J., 17: 3351-3362, 1998.
THANKs

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ONCOLYTIC VIRUSES AS AN ANTICANCER AGENT........ _________

  • 1. ONCOLYTIC VIRUSES AS ANTICANCER AGENTS BY ADEOYE OPEYEMI ADURAGBEMI
  • 2. OUTLINE ü INTRODUCTION ü HISTORICAL BACKGROUND ü ONCOLYTIC VIRUSES AS AN ANTICANCER AGENT ü GENOMIC ORGANISATION OF SOME SELECTED ONCOLYTIC VIRUS ü MECHANISMS OFANTITUMORAL EFFICACY OF ONCOLYTIC VIRUSES ü TUMOR SELECTIVITY/SPECIFICITY ü ONCOLYTIC VIRUSES AND THEIR GENETIC MANIPULATIONS IN CLINICAL TRIALS ü ADVANTAGES AND DISADVANTAGES OF ONCOLYTIC VIRUSES ü BENEFITS AND LIMITATIONS OF GENETIC MANIPULATION WITH POTENTIAL SOLUTIONS ü FUTURE PROSPECT OF ONCOLYTIC VIRUSES ü CONCLUSION AND RECOMMENDATION ü REFERENCES
  • 3. INTRODUCTION v Cancer continues to be a leading cause of death, accounting for 8.2 million deaths worldwide in 2012. v Cancer mortality with incidence projected to rise from an estimated 12 million cases in 2012 to 22 million within the next twenty years (Bradley et al., 2014 ). v Recently according to the WHO, over 100,000 Nigerians are diagnosed with cancer annually and about 80,000 die from the disease. v WHO estimated that 240 Nigerians die per day or 10 per hour die from cancer disease. v The Nigerian cancer death ratio of 4 in 5 is one of the worst in the whole world
  • 4. v Early human trials using viruses in anti-cancer treatments initially yielded excitement as tumor regression was often seen without toxicity. v However, tumor regression was followed by tumor progression during the late stages of these trials approaches. v 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. CONTD…
  • 5. TABLE 1: CLINICAL VIROTHERAPY: FOUR HISTORICALLY SIGNIFICANT CLINICAL TRIALS Abbreviations: IA, intra-arterial; IT, intratumoral; IV, intravenous; TC, tissue culture. Source:Kelly andRussell,2007. Year(s) Virus Disease No. of patient s Administration Outcome Side effect 1949 Hepatitis B virus Hodgkin's disease 22 Parenteral injection of unpurified human serum, tissue extract 4/22 reduction in tumor size, 7/22 improved in clinical aspect of disease; 14/22 developed hepatitis; Fever, malaise, death (1 confirmed) 1952 Egypt 101 virus (early passage West Nile) Advanced, unresponsive neoplastic disease 34 IV, intramuscular injection of bacteriologically sterile mouse brain, chick embryo, human tissue 27/34 infected; 14/34 oncotropism; 4/34 (transient) tumor regression Fever, malaise; mild encephalitis (2 confirmed) 1956 Adenovirus adenoidal- pharyngeal- conjuctival virus (APC) Cervical carcinoma 30 IT, IA, IV injection of TC supernatant 26/30 inoculations resulted in localized necrosis Vaginal hemorrhage; infrequent (3/30) fever, malaise 1974 Mumps virus (wild- type, non- attenuated) Terminal cancers; gastric, pulmonary, uterine account for more than 50% 90 External post- scarification; IT; IV; oral; rectal; inhalation of purified human saliva or TC supernatant 37/90 complete regression or decrease >50%; 42/90 decrease <50% or growth suppression; 11/90 unresponsive 7/90 adverse reactions: bleeding, fever
  • 6. ONCOLYTIC VIRUSES v Literally, Onco- refers to cancer while Lytic- refers to killing v Oncolytic viruses (OVs) are viruses that have the ability to specifically infect and lyse cancer cells, while leaving normal cells uninfected. v Examples are üAdenovirus üVaccinia virus üVesicular stomatitis virus (VSV) üSeneca valley virus (SVV) üReovirus üMaraba virus üNewcastle disease virus (NDV)
  • 7. CHARACTERISTICS OF IDEAL ANTICANCER VIRUS vSpecific in action vReplicate only in tumor cells vHighly lytic vAble to induce anti-tumor immune response to the host cells.
  • 8. Figure 1: Generalised diagram of the cancer specificty of oncolytic viruses (Mode of action) The diagram above illustrates how oncolytic virus encounter normal cells and cancer cells. Source: Wilkipedia online(modified 2015).
  • 9. Table 2: Mechanisms of antitumoral activity of oncolytic viruses Mechanism Examples 1. Direct cell lysis due to viral replication Adenovirus ,Herpes simplex virus 2. Direct cytotoxicity of viral proteins Adenovirus E4ORF4,E3KPO11.6kD 3. Induction of antitumoral immunity • Nonspecific (e.g., TNF) Adenovirus (E1A) • Specific (e.g., CTL response) Herpes simplex virus 4. Sensitization to chemotherapy and radiation therapy Adenovirus (E1A) 5. Transgene expression Adenovirus (AdTK-RC) Herpes simplex virus (rRp450) Vaccinia virus (GM-CSF) Source: Kirm, 1996.
  • 10. GENETIC MANIPULATION OF ONCOLYTIC VIRUSES v The resistance of cancers to conventional therapies has inspired the search for novel strategy called gene therapy. v based on manipulation of viral gene / viruses as genetic vectors. v These involve use of replication-competent viruses. v This require understanding genome of the virus to be use(Ring, 2002).
  • 11. CONTD… v Knowledge of the pathogenesis of virus diseases and ability to manipulate specific regions of viral genomes have allowed the construction of viruses that are attenuated in normal cells but retain their ability to lyse tumor cells and also will enhance an immune response against it. v Such manipulations include modifying the ability of the viruses to bind to, or replicate in a particular cell type while others have involved the construction of replication-competent viruses encoding suicide proteins or cytokines (Ring, 2002).
  • 12. MECHANISMS OF TUMOR SELECTIVITY/SPECIFICITY There are six general mechanistic approaches to tumor-selective replication described to date. These include: (a) The use of viruses with inherent tumor selectivity (e.g., NDV, reovirus, VSV(Coffey et al., 1998) (b) Deletion of entire genes e.g. HSV, adenovirus, vaccinia (Mastrangelo, et al., 2000) (c) Replacement of functional gene regions e.g. adenovirus, poliovirus (Gromeier et al., 2000).
  • 13. CONTD… (d) Engineering of tumor/tissue–specific promoters e.g. adenovirus, HSV (Miyatake, et al., 1997) (e) Modification of the viral coat to target uptake selectively to tumor cells (e.g., adenovirus, poliovirus) (f) Insertion of genes such as those encoding suicide proteins, tumour suppressor proteins or cytokines into tumour cells by means of a genetic vector.
  • 14. CRITERIA FOR SELECTING ONCOLYTIC VIRUSES AGAINST TUMORS vPathogenesis of the oncolytic virus (biological behavior of the virus) vTumor type vTropism of the virus in relation to location of the tumor vPresence of viral receptor in the target tumor cells.
  • 15. GENOMIC ORGANISATION OF ONCOLYTIC VIRUS Genomic diversities occur among the oncolytic viruses v DNA viruses such as Herpes simplex virus-1, Myxoma virus and vaccinia virus v RNA viruses such as vaccinia virus, Newcastle disease virus, Seneca Valley Virus, Reovirus and Maraba virus. v It is worthy knowing that most of the oncolytic viruses are RNA Virus because of their small virion size.
  • 16. Figure 2: Morphology and genomic organisation diagram of Adenovirus. dsDNA, Adenoviridae,nE Icosahedral symmentary, with 20 faces, CAReceptor, Particle-70-90nm in Diameter CV706 (PSA),ONYX-015 Source: Banko and Harrach 2003.
  • 17. Figure 3:GENOMIC ORGANISATION OF MARABA VIRUS AND VESICULAR STOMATITIS VIRUS Source: Brun J. et al., 2010 Rhadovirus family Vesiculovirus genus -ssRNA, E unsegmented 3’ NPMGL5’ NonPathogenic in human Sensitive to interfron 3 5 , ,
  • 18. Figure 4:GENOMIC ORGANISATION OF HERPES SIMPLEX VIRUS HSV-neurotropic,DNA,Herpesviridae, nonEssential 30kb-15K,NV1020. UL56genes (4,6mp of Us),Us12genes, Repeat unit of a-c
  • 19. Figure 5:GENOMIC ORGANISATION OF VACCINIA VIRUS Source: Baroudy and Moss, 1982.
  • 20. Figure 6: Morphology and genomic organisation diagram of Measles virus. Source: Rima et al.,2009 -ssRNA, Paramyxo, Morbillivirus 3 gene code for H ,M,F W.T –CD150 Attenuated MV edm- CD 46
  • 21. Figure 7:THE GENOMIC STRUCTURE OF POLIOVIRUS TYPE 1 +ssRNA,nE,PvEnterovirus 7500nucleotide Long CD155r (PVR),30nm viral Particles PV1(RIPO). Source: Goetz and Gromeier, 2010
  • 22. Poliovirus as an oncolytic agent v Poliovirus is a natural neuropathogen, making it the obvious choice for selective replication in tumors derived from neuronal cells. v Poliovirus replicates in the GIT, the virus invades the central nervous system (CNS) where it targets predominantly motor neurons, thereby causing paralysis and even death (poliomyelitis). v Generally, poliovirus replicates efficiently in nearly all tumor cell lines tested, which has led to the suggestion that it may be suitable for the treatment of different cancers. v However, the possibility that poliovirus can cause poliomyelitis calls for significant neuro attenuation to avoid collateral neurologic complications in cancer treatment.
  • 23. v Poliovirus has a positive -strand RNA genome, the translation of which depends on a tissue-specific internal ribosome entry site (IRES) within the 5' untranslated region of the viral genome, which is active in cells of neuronal origin and allows translation of the viral genome without a 5’ cap replaced the normal poliovirus IRES with a rhinovirus IRES, altering tissue specificity. The resulting PV1(RIPO) virus was able to selectively destroy maglinant glioma cells, while leaving normal neuronal cells untouched (Gromeier et al. 2000)
  • 24. TABLE 3: SUMMARY OF SOME SELECTED ONCOLYTIC VIRUSES AND THEIR GENETIC MANIPULATIONS IN CLINICAL TRIALS Virus Deletions/Mutations Foreign gene/promoter insertion Tumors targeted in studies VACCINIA VIRUS JX-594 Deletion of both copies of TK gene Human GM-CSF and lacZ insertion into the TK gene region EWS, lymphoma, NB, RMS, Wilms tumor . PhaseI/II HSV-1 G207 Deletion in both copies of γ134.5 gene and disabling lacZ insertion in UL39 None Phase II Glioma, MDB, OST, RMS, Colorectal cancer HSV1716 Deletion in both copies of γ134.5 gene None Non-CNS solid tumors M002 Deletion in both copies of γ134.5 gene Murine IL-12 gene insert Glioma, RMS rQNestin34.5 Deletion in γ134.5 gene and UL39 ICP-34.5 under control of a synthetic nestin promoter Glioma, NB rQT3 Deletions in ICP6 and γ134.5 gene Tissue inhibitor of MMP3, HSV-1 immediate early 4/5 promoter NB, MPNST
  • 25. Table continue HSV-1 VAE Deletion in both copies of γ134.5 gene Endostatin–angiostatin fusion gene insert Glioma Chase-ABC Deletion of both copies of γ134.5 and in-frame gene- disrupting insertion of GFP within the ICP6 gene Inserted Chase-ABC cDNA under the viral IE4/5 promoter within the ICP 6 locus Glioma Measles virus Engineered to target CD46 on tumor cells Phase I Brain,MM CNS tumor Adenovirus OBP-301 Deletion of native E1 promoter of Ad5 Human hTERT promoter to drive E1A and E1B expression linked to an internal ribosome entry site Phase III OST AD5/3- Cox2L-D24 Deletion of Rb binding region from the E1A gene Inserted cyclooxygenase -2 (COX- 2) promoter NB ICOVIR-5 Deletion of Rb binding region from the E1A gene Substitution of the E1A promoter for E2F-responsive elements, RGD-4C peptide motif insertion NB
  • 26. Table continues Abbreviation:Ad5, adenovirus serotype 5; CIK-vvDD, cytokine-induced killer double-deleted vaccinia virus; CNS, central nervous system; EWS, Ewing's sarcoma; GM-CSF, granulocyte colony-stimulating factor; hTERT, human telomerase reverse transcriptase; IL;interleukin; MDB, medulloblastoma; MMP3, metalloproteinases-3; MPNST; malignant peripheral nerve sheath tumor; MYXV,-myxoma virus; NB, neuroblastoma; OST, osteosarcoma; RB, retinoblastoma; RGD, arginine-glycine-aspartic acid; RMS-rhabdomyosarcoma; SVV, Seneca valley virus; TK, thymidine kinase; VSV, vesicular stomatitis virus Delta-24-RGD Deletion of Rb binding region from the E1A gene Inserted RGD into the H1 loop of the fiber protein Glioma CRAd-Survivin- pk7 Deletion of native E1 promoter of Ad5, polylysine modification in the fiber knob Human survivin promoter to drive E1 expression Glioma Reovirus type 3 Dearing None None MDB, RMS, OST, EWS Seneca Valley Virus SVV-001 None None EWS, glioma, MDB, NB, rhabdoid tumor, RB, Wilms tumor. Phase I Source: Friedman et al., 2011.
  • 27. Table 4: Specific Advantages and Disadvantages of different oncolytic viruses Virus Virus type Insertio n size Advantage Disadvantages HSV-1 (152 kb) DNA 40-50kb Neurotropic Ability to infect a wide variety of tumors Large amount of nonessential genes can be replaced with foreign DNA to enhance cytotoxicity Clinically available antiviral agents Systemic delivery may be limited by preexisting immunity and hepatic adsorption Adenovirus (36 kb) DNA 7.5kb Ability to infect a wide variety of tumors with modifications of the fiber knob Large amount of nonessential genes can be replaced with foreign DNA to enhance cytotoxicity CAR variability in human cancers Systemic delivery may be limited by preexisting immunity, hepatic adsorption and toxicity. Small insert capacity Reovirus RNA ? Wild-type virus causes mild to no disease Systemic delivery possible Activated Ras or Ras effectors necessary Inability to enhance infection with foreign DNA Maraba virus RNA ? Ability to boost adaptive antitumor immunity. Does not cause human disease Limited preclinical data. unknown mechanism of action
  • 28. VV (187 kb) DNA 25kb Ability to infect a wide variety of tumors Large amount of nonessential genes can be replaced with foreign DNA to enhance cytotoxicity Inefficient systemic delivery NDV RNA ? Targets cancer cells with loss of interferon responsiveness. Ability to express foreign DNA to enhance cytotoxicity Used safely in children with recurrent gliomas. Immune-mediated clearance of virus. Transgene insertion reduces viral replication. MYXV DNA ? Targets cancer cells with altered Akt signaling Does not cause human disease Limited preclinical data in pediatric cancers VSV RNA ? Targets cancer cells with loss of interferon responsiveness Limited preclinical data in pediatric cancers Uncertain tumor selective oncolytic effect SVV RNA ? Virus does not cause human disease Mechanism of infection unclear Inability to enhance infection with foreign DNA Source: Friedman et al., 2011
  • 29. GENERAL BENEFITS AND LIMITATIONS OF ONCOLYTIC VIRUSES Benefits 1. Effective tumor removal 2. Limited or no side-effects 3. Selectivity 4. Cost-efficiency Limitations 1. Revertant of mutant virus (accidental emergence of a new viral pathogen) 2. Deletion of viral genes 3. Anti Immune response of the host. 4. According to Russell, 1994, the limitation to Oncolytic viruses are the safety concerns arising from the use of it, for human cancer therapy, these can be divided into two areas: v Risk to the patient v Risk to the population (Serious epidemics)
  • 30. Possible solutions v Use of a competent replicative virus v further attenuation of the virus v Suppressing the host immune response or enabling the virus to evade immune recognition v Use non-transmissible virus and preferably derived from a virus to which the population is generally immune. v use of an ideal oncolytic virus which should be selective for the tumor, nonpathogenic for normal host tissues, non- persistent and genetically stable (Russell, 1994).
  • 31. PROSPECT OF ONCOLYTIC VIRUSES v Despite the fact that Oncolytic viruses may be effective against cancer cells without any supplements; the combination of chemotherapy or radiation therapy with oncolytic virus may be highly efficient in cancer destruction. v Oncolytic viruses can be used as vector for the delivery of vaccine. v There is now a compelling need to develop new classes of anticancer agents with little or no side effect.
  • 32. Conclusion and Recommendation v Cancer virotherapy is a rapidly maturing field that will be an integral part of future cancer therapies. v With the advent of genetic engineering a wide range of viruses are being manipulated and evaluated into various types of cancers. v Many clinical trials around the world have had good results with high success rates using oncolytic virotherapy, and many more clinical trials are in progress with new viral vectors for the treatment of intractable cancers. v Nigeria should not be left behind! It is thus recommended that our research centers should be actively involved in clinical trials of these anticancer agents.
  • 33. REFERENCE Baroudy B M, Moss B, (1982). Sequence homologies of diverse length tandem repetitions near ends of vaccinia virus genome suggest unequal crossing over Brun J, Dan M,Charles L, Kang H,Theresa F, Harold A, John C , J. Andrea M, Douglas M,and David F S (2010).Identification of Genetically Modified Maraba Virus as an Oncolytic Rhabdovirus Christopher . A.Ring (2002), cytolytic viruses as potential anti-cancer agents Coffey M, Strong J, Forsyth P, Lee P. Reovirus therapy of tumors with activated ras pathway Science 1998 282: 1332–1334 | Article | PubMed | ISI | ChemPort Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E. Intergeneric poliovirus recombinants for the treatment of malignant glioma [see comments] Proc Natl Acad Sci USA 2000 97: 6803–6808 | Article | PubMed | ChemPort |
  • 34. Hales LM,Knowles NJ,reddy PS,Xul, HayC, Hallenback PL,(2008) Complete genome sequence analysis of Seneca Valley virus-001, a novel oncolytic picornavirus. Johnsonston JB, Barrett JW, Nazarian S H, Goodwin M,Ricuito D,Wang G,Mcfadden G,(2005) A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection Kim M, et al. 2011. Attenuated reovirus displays oncolysis with reduced host toxicity. Br. J. Cancer 104:290–299 Mastrangelo M, Eisenlohr L, Gomella L, Lattime E. Poxvirus vectors: orphaned and underappreciated J Clin Invest 2000 105: 1031– 1034 | PubMed | ISI | ChemPort |
  • 35. Novelli, A. & Boulanger, P. A. (1991). Deletion analysis of functional domains in baculovirus-expressed adenovirus type 2 fiber. Virology 185, 365-76 Osada S., Carr B. I. Critical role of extracellular signal-regulated kinase (ERK) phospholylation in novel vitamin K analog-induced cell death. Jpn. J. Cancer Res., 91: 1250-1257, 2000 Rima BK AND Duprex W.P (2009).The m easles virus replication cycle. Curr Top Microbiol Immunology.
  • 36. Russell S(1994). Replicating vectors for cancer therapy: a question of strategy. Seminars in cancer biology.5:437–443 Russell,S.(2002). Cancer gene therapy, RNA viruses as virotherapy agents Rux, J. J. & Burnett, R. M.(2004). Adenovirus structure. hum Gene Ther 15, 1167-76 Stouten, P. F., Sander, C., Ruigrok, R. W. & Cusack, S. (1992). New triple-helical model for the shaft of the adenovirus fibre. J Mol Biol 226, 1073-84 Strong J. E., Coffey M. C., Tang D., Sabinin P., Lee P. W. K. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J., 17: 3351-3362, 1998.