|
Table
I – OVs targeting oncogenic ras or defective IFN pathways.
|
|
Virus (Company, if
known)
|
Viral gene defect
|
Cellular Target
|
Tumor models
|
References
|
|
Influenza A
|
NS1
|
PKR
|
Melanoma
|
(1)
|
|
HSV1mutants:
R3616, 1716, G207 (Medigene, Inc.), MGH1
|
ICP34.5
|
Protein phosphatase 1a, Defective interferon signaling.
|
Brain, Colorectal, ovarian,
lung, prostate, breast
|
(2, 3)
|
|
Reovirus (Oncolytics
Biotech., Inc.)
|
None
|
Overactive
Ras pathway
|
Brain, ovarian, breast,
colorectal
|
(4-7) .
|
|
VSV
|
None
|
Defective
Interferon signaling
|
Melanoma
|
(8)
|
|
Newcastle
disease virus (Provirus)
|
None
|
Overactive
Ras pathway
|
Fibrosarcoma, Neuroblastoma
|
(9)
|
|
Table
II - OVs targeting defective p16 tumor suppressor pathways.
|
|
Virus (Company, if
known)
|
Mutated viral gene
|
Cellular target
|
Effect
|
References
|
|
Adenovirus D24
and dl922-947 (Onyx Pharmaceuticals)
|
E1A-CR2
domain
|
PRB
|
Viral replication restricted
to pRB-defective mutants
|
(10, 11)
|
|
Adenovirus CB106
|
E1A-CR1
and CR2 domains
|
PRB, p300, p107, p130
|
In keratinocytes, viral
replication restricted to papillomavirus E6/E7 expressors
|
(12)
|
|
Adenovirus ONYX-411(Onyx
Pharmaceuticals)
|
a)
E1A-CR1
b)
E2F promoter driving E1A and E4 genes
c)
E3 deletion
|
PRB
and upregulated E2F transcription factor
|
Increased dependence
of virus replication on overactive E2F
|
(13)
|
|
HSV: hrR3, rRp450, HSV1yCD,
MGH1, G207 (Medigene, Inc.), G47D)
|
Ul39 (ICP6)
|
RR
activity elevating dNTP pools
|
Viral replication depends
on dNTP pools
|
(14, 15)
|
|
HSV Myb34.5 (Prestwick
Scientific, Inc.)
|
a)
UL39 (ICP6)
b)
B-Myb (E2F-responsive) promoter driving g34.5 gene)
|
RR activity elevating
dNTP pools and upregulated E2F transcription factor
|
Increased viral replicative
dependence on E2F activity
|
(16, 17)
|
|
Vaccinia vvDD-GFP
|
TK gene
|
Elevated dTTP (due to
cellular TK?)
|
Viral replication restricted
to cells with dTTP pools
|
(18, 19)
|
|
Table
III- OVs targeting defective p53 tumor suppressor pathway.
|
|
Virus (Company, if
known)
|
Mutated viral gene
|
Cellular target
|
Effect
|
References
|
|
Adenovirus ONYX-015 (Onyx Pharmaceuticals)
|
E1B-55Kd
|
p53
|
Viral replication restricted
to p53-defective mutants
|
(20)
|
|
Adenovirus 01/PEME (Canji)
|
1) p53 promoter driving expression of E2F antagonist
2) E1A-CR1 p300 binding-domain
3) E3 deletion
4) Extra Major Late Promoter driving expression of E3-11.6 Kd
|
p53, p300.
|
Expression
of E2 and subsequent viral genes dependent on loss of p53
function; wild-type p53 function enhanced by p300 coactivation;
increased adenoviral release and cell death by adenoviral
death protein (21)
|
(22)
|
|
AAV
|
AAV unusual DNA structure
is precipitating factor
|
p53/
p21
|
Lack
of G2/M arrest in p53-defective cells, infected with AAV,
causes cell death
|
(23)
|
|
Table
IV- Targeting of OV with tumor-specific promoters.
|
|
Virus (Company, if
known)
|
Tumor-specific Promoter
|
Viral gene
|
Effect
|
References
|
|
Adenovirus CV706 (Calydon,
Inc.)
|
PSA
(prostate)
|
E1A
|
Replication restricted
to prostate tissue
|
(24)
|
|
Adenovirus CN787 (Calydon,
Inc.)
|
a)Rat
probasin promoter for E1A
b)
PSA for E1B
|
E1A and E1B
|
Same as above
|
(25, 26)
|
|
Adenovirus CV980 (Calydon,
Inc.)
|
AFP
(hepatocellular carcinoma)
|
E1A and E1B
|
Replication restricted
to hepatic tumors.
|
(27)
|
|
Adenovirus ONYX-411 (Onyx
Pharmaceuticals)A
|
E2F1 promoter (most tumors)
|
E1A
and E4
|
Increased dependence
of virus replication on overactive E2F
|
(13)
|
|
Adenovirus 01/PEME (Canji
Inc.)B
|
p53
promoter (most tumors)
|
E2F antagonist.
|
Expression
of E2 and subsequent viral genes dependent on loss of p53
function
|
(22)
|
|
CG8840 (Cell Genesys,
Inc.)
|
Uroplakin II (bladder)
|
E1A and E1B
|
Replication restricted
to bladder cancer
|
(28)
|
|
KD1-SPB
|
Surfactant protein B
|
E4
|
Replication improved
in lung tumors
|
(29)
|
|
HSV Myb34.5 (Prestwick
Scientific, Inc.)A
|
B-Myb promoter (most
tumors)
|
g34.5 (ICP34.5)
|
Improved replication
in tumors
|
(16, 17)
|
|
HSV DF3g34.5
|
DF3 promoter
|
g34.5 (ICP34.5)
|
Improved replication
in MUC1-positive pancreatic and breast tumor cells.
|
(30)
|
|
HSV G92A
|
Albumin promoter
|
ICP4
|
Replication restricted
in hepatoma
|
(31)
|
A OV
discussed in more detail in Table 3
B OV discussed in more
detail in Table 4
|
Table
V- Targeting with “tumor-selective” infection.
|
|
Virus
|
Redirected viral ligand
|
Cellular target
|
Effect
|
References
|
|
Dual Adenovirus systemA:
AdsCAR-EGF + D24
|
Bispecific-
antibody binding adenovirus fiber to EGFR
|
EGFR
|
Redirects viral infection
to EGFR-expressing cells
|
(32)
|
|
Adenovirus: Ad5-D24RGD
|
H1-loop
in Fiber of Ad modified by incorporation of RGD
|
Integrin
|
Redirects
viral infection to integrin-expressing cells.
|
(33)
|
|
D24 or ONYX-015B
|
Infusion of bispecific
antibodies to fiber and EGFR
|
EGFR
|
Redirects viral infection
to EGFR-expressing cells
|
(34)
|
|
Ad 5/35
|
Fiber of adenovirus serotype
35 substituted into adenovirus serotype 5
|
Unknown
|
Redirects viral infection
away from CAR and towards an unidentified cellular receptor
present in human breast cancer
|
(35)
|
A Consists
of a 1:1 mix of replication-defective, sCAR-EGFR secreting adenovirus
and the OV, AdD24 (Table 4). BDiscussed
in more detail in Table 5.
|
Table
VI- Other mechanisms of OV targeting.
|
|
Virus
|
Defect in viral gene
|
Effect
|
Oncolytic mechanism
|
References
|
|
Vaccinia vvDD-GFP
|
Vaccinia
Growth Factor
|
Cannot
prime neighboring cells to divide
|
Only
dividing tumor cells will replicate, because normal cells
are not “primed” by VGF
|
(18)
|
|
Poliovirus PV1(RIPO)
|
Substitutes
poliovirus IRES element with rhinovirus 2 IRES
|
Loss
of neurovirulence, because neurons cannot translate mRNA with
substituted IRES
|
Tumor
cells can still propagate virus
|
(36)
|
|
Adenovirus E1-
|
E1
|
Does
not replicate
|
Tumor
cells can complement the E1 defect
|
(37, 38)
|
|
Adenovirus Ad.IR-BG
|
E1
defect with inverted repeats flanking reporter transgene in
antisense orientation to promoter
|
DNA
replication rearranges the construct so that promoter is 5’
to reporter transgene
|
Adenoviral
replication only occurs in tumor cells that complement the
E1 defect
|
(39)
|
|
Measles, mumps, Sindbis,
Sendai
|
None
|
Tumor
lysis
|
Unknown
|
(40, 41)
|
|
Table
VII – OVs that express anti-cancer cDNAs.
|
|
Virus
|
Viral gene defect
|
Anticancer cDNA
|
Prodrug> Metabolite
|
Effect
|
Reference
|
|
HSV1A: hrR3, MGH1,
G207 (Medigene, Inc.)
|
ICP6 and/or
ICP34.5
|
TK
|
Ganciclovir>GCV-Phosphate
|
Predominant
anticancer action in some situations, but increased antiviral
action in others (figure 5)
|
(42-49) .
|
|
HSV1: rRp450
|
ICP6
|
CYP2B1
|
Cyclophosphamide>
Phosphoramide Mustard
|
Predominant
anticancer action + immunosuppressive effects.
|
(15)
|
|
Adenovirus: FGR
|
E1B55kD
|
Fused TK-CD gene
|
Ganciclovir> GCV-Phosphate
+ 5-fluorocytosine> 5fluorouracil
|
Combination
of FGR, GCV, 5FC and radiation shows predominant anticancer
action
|
(50)
|
|
HSV1: Fu-10
|
Unknown
|
Fusogenic glycoprotein
|
Not applicable
|
Enhanced fusion of cell membranes caused by replicating
virus increases anticancer effect
|
(51)
|
|
Adenovirus: ad5/IFN
|
E3
|
Interferon
|
Not applicable
|
Increased
anticancer effect compared to control E3-deleted adenovirus
|
(52)
|
|
Adenovirus; Ad.TKRC,Ad.OW34
|
E1B55KD
|
TK
|
Ganciclovir> GCV-Phosphate
|
Contradictory
anticancer effects
|
(53, 54)
|
|
Adenovirus:
Ig.Ad5E1+.E3TK
|
E3-19K
|
TK
|
Ganciclovir> GCV-Phosphate
|
Increased
anticancer effect in glioma
|
(55)
|
|
HSV1: Mix of G207 + Defective
HSv-IL2B
|
ICP6 and ICP34.5
|
IL2
|
Not applicable
|
At
low dose, the mix was more effective than either virus alone
|
(56)
|
|
HSV1: NV1042
|
Complexc
|
IL12
|
Not applicable
|
Increased
anticancer effect
|
(57)
|
|
HSV1: Mix of G207 + Defective
HSV-soluble B7-1B
|
ICP6 and ICP34.5
|
Soluble B7-1
|
Not applicable
|
Increased
anticancer effect
|
(58)
|
|
HSV1: HSV1yCD
|
ICP6
|
Yeast cytosine deaminase
|
5-fluorocytosine>
5-fluorouracil
|
Increased
anticancer effect minimal antiviral effect
|
(59)
|
|
Vaccinia: VCD
|
TK
|
Bacterial cytosine deaminase
|
5-fluorocytosine>
5-fluorouracil
|
Increased
effect at low viral dose
|
(60)
|
|
HSV1
|
ICP34.5
|
IL4, IL12, IL10
|
Not applicable
|
Increased
anticancer effect for IL12 and IL4, but antagonistic effect
for IL10
|
(61, 62)
|
A See Figure
3 for detailed description
B Represents
a 1:1 mix of OV g207 and replication-defective HSV1 expressing
cytokine cDNA. Based on the “Piggyback” concept, first shown in
ref. 140
C An intertypic
HSV11/HSV12 recombinant derived from R7020 (NV1020 – Medigene,
Inc.) resulting in deletion of: Ul55, UL56, one copy of
ICP0, ORF 0 and ORF P and reinsertion of: TK with ICP4
promoter; HSV12 glycoprotein G,D,I,E 141
|
|
![[Divider]](images/barrule.gif){kind=small}
