Microorganisms that kill cancer cells!
Do you think you are just eating vegetables & Fruits?!
What about
the microorganisms within it
Did you
know that some microorganisms kill cancer cells!
It could be bacteria, Fungi, protozoa or even
a VIRUS!
There are oncolytic
microorganisms that share certain traits which are selecting cancer cells and destroying
it while leaving
healthy cells and others destroy the healthy cells too!
There are
certain microorganisms that have insignificant damage to healthy cells and also
could be genetically modified and enhanced easily now
Maybe it’s one of the factors that people who are
eating and juicing (RAW) vegetables and fruits get cured From cancer!
Did we research all the microorganisms?
What about abusing antibiotics and its effect on
these microorganisms?
Here Researchers at The Ottawa
Hospital have launched a clinical trial in the fight against cancer, using an
unlikely duo: the common cold and a Brazilian sand fly (Very Promising Results)
REOVIRUS
Reovirus
naturally infects the lining of the lungs and the bowels of humans from time to
time. For example, the small intestine is a natural place for reovirus to
survive and proliferate as new cells are constantly being regenerated and shed.
 |
Reovirus
naturally grows in ... "the lining of the lungs and the bowel where the
cells are bathed in EGF and they are in sort of a pseudo state of Ras
activation. The reason these isn't a pathology associated with that is that
those cells die, they self-destruct within 24-36 hours after division anyway
and so it is about the same time that the virus will actually kill the cell
population. It's the natural reservoir for these viruses" - Dr. Brad
Thompson, April 2005.
Putative
stem cells (dark blue) reside immediately above the Paneth cells (yellow)
near the crypt bottom. Proliferating progenitor cells occupy the remainder of
the crypt. Differentiated cells (green) populate the villus, and include
goblet cells, enterocytes and entero-endocrine cells.
|
Reovirus
depends on the cells it infects to produce the proteins it needs to make more
copies of itself. Reovirus does not command the nucleus of the host cell to
produce its mRNA as many other viruses do, but produces its own mRNA from the
reovirus core. A thick cloud called a viral factory forms inside the cell where
the proteins are assembled back into reovirus particles.
Cells have natural defenses against reovirus.
- Some cells that are
penetrated by a reovirus particle react by killing themselves off by
entering an apoptotic state and are devoured by the immune system.
- Some immune cells
simply kill the virus and use it as a marker to kill other cells that
display the same markers (dendritic cells).
- Other immune cells
create small antibodies to the virus that attach to the virus outer
proteins and mark it for distruction even before the virus enters a cell.
- Most normal cells
will automatically prevent the mRNA from generating more reovirus
particles because of a molecule called PKR circulating within the cell.
Cells in
certain unusual states (as cancerous cells often are) appear to be especially
poor at stopping the reovirus from replicating. In fact, in many cancerous
cells, reovirus is able to replicate and produce 1000's of prodigy virus out of
that one cell before exploding out of the cell in a process called cell lysis.
_______________________________________
In 1890,
Coley, a New York physician, found that several patients with inoperable tumors
exhibited tumor regression subsequent to being inoculated with Streptococcus pyogenes. However, the effect was not as
great as to eradicate the disease
In 1935,
Connell observed tumor regression in advanced cancer during therapy using
sterile filtrates from Clostridium histolyticum; the
author attributed these results to the production of enzymes
In 1947, the
first study concerning the deliberate injection of Clostridium was published (13). Nonetheless, this field was stagnant due to certain
drawbacks (14). It was not until 1976, when Morales, Eidinger and Bruce
reported successful treatment of bladder cancer with bacillus Calmette-Guérin
(BCG), that this field began to increase rapidly
Since the very
beginning of modern medicine in the 19th century physicians
observed tumor regression coinciding with infections. It was a time when the
basics of microbiology were being settled and a distinction between bacteria
and viruses was not so clear. Biological cancer therapies using viruses or
bacteria proved to be beneficial to some patients but lost the struggle for
attention with the rise of chemotherapy and radiotherapy.
Half a century
had to pass until microbiology was developed enough and genetic modification
started to be possible.
In the search
of better therapies, science returned to the abandoned ideas. Using modern
techniques improves previous weaknesses to carve potential therapies. Luckily
both bacteria and viruses are fairly easy for genetic manipulation and there
are plenty possible species to research.
Oncolytic
virus therapy has recently been recognized as a promising new therapeutic
approach for cancer treatment. An oncolytic virus is defined as a genetically
engineered or naturally occurring virus that can selectively replicate in and
kill cancer cells without harming the normal tissues. In contrast to gene
therapy where a virus is used as a mere carrier for transgene delivery,
oncolytic virus therapy uses the virus itself as an active drug reagent.
The concept of oncolytic virus therapy
has existed for some time (Fig. (Fig.1).1). Tumor regression has often been observed
during or after a naturally acquired, systemic viral infection.1, 2 In 1949, 22 patients with
Hodgkin's disease were treated with sera or tissue extracts containing
hepatitis virus.3 Between 1950 and 1980, many
clinical trials were performed in attempts to treat cancer with wild type or
naturally attenuated viruses, including hepatitis. West Nile fever, yellow
fever, dengue fever and adenoviruses.4 However, these viruses were not
deemed useful as therapeutics reagents because, in those days, there was no
known method to control the virulence and yet retain viral replication in
cancer cells.
Milestones
of oncolytic virus therapy development.
It is now recognized, because
protection mechanisms against viral infection (e.g. interferon‐beta signal pathway)
are impaired in the majority of cancer cells,5 that most viruses can replicate
to a much greater extent in cancer cells than in normal cells. Therefore,
getting a virus to replicate in cancer cells is not a problem: What is
difficult is making a virus not replicate in normal cells at all, while
retaining its replication capability in cancer cells. Attempts to achieve
cancer cell‐specific replication
have been undertaken either by selecting a virus that is non‐virulent in humans or
by engineering the virus genome (Fig. (Fig.2).2). Representing the former strategy is
Reolysin, a wild‐type
variant of reovirus that exhibits oncolytic properties in cells with activated
Ras signaling with limited virulence in normal human cells. The latter strategy
is, however, better suited to achieving strict control of viral replication. In
1991, Martuza et al.6 demonstrated that a genetically
engineered herpes simplex virus type I (HSV‐1) with a mutation in the thymidine
kinase (TK) gene replicated selectively in cancer cells and was useful
for treating experimental brain tumors. Their findings opened up a whole new
area of oncolytic virus development that involves designing and constructing
the viral genome. During the past two decades of thriving development, probably
the most important finding regarding oncolytic virus therapy was that a
systemic tumor‐specific
immunity is efficiently induced in the course of oncolytic activities.7, 8 This phenomenon is now widely
recognized as the common feature for all oncolytic virus therapy that is
expected to play a major role in prolonging the survival of cancer patients
(Fig. (Fig.33).
Structures
of major oncolytic viruses. Boxes represent inverted repeat sequences flanking
the long (UL) and short (US) unique sequences of HSV‐1 DNA in T‐Vec and G47∆. T‐Vec has an insertion
of human GM‐CSF in
both ...
Mechanisms
of action of oncolytic virus therapy. Local replication of oncolytic virus
induces specific antitumor immunity in the course of its oncolytic activities
that act on remote lesions. A combination with immune checkpoint inhibitors or
chemotherapy ...
To date, two genetically engineered
oncolytic viruses have been approved for marketing as drugs. One is Oncorine
(H101, the same construct as ONYX‐015),9 an E1B‐deleted adenovirus,
which was approved in China for head and neck cancer and esophagus cancer in
2005.10, 11 The use and clinical data of
Oncorine is so far limited to China. The other is T‐Vec (talimogene
laherparepvec, IMLYGIC, formerly OncoVEXGM‐CSF), which was approved
for melanoma by the FDA in the USA in October 2015 and was subsequently
approved in Europe in January 2016 and in Australia in May 2016 (Fig. (Fig.11).12, 13 Many clinical trials using T‐Vec are currently
performed worldwide by the pharmaceutical company in order to expand its
application and also to expand countries for marketing. This review focuses on
those oncolytic viruses under development that are likely to become treatment
options in the near future (Table 1).
Summary
of major oncolytic viruses under clinical development
Genetically engineered oncolytic
viruses
With the development of modern
techniques of genetic engineering and increasing knowledge regarding the
functions and structures of viral genes, designing and manipulating the viral
genome to create a non‐pathogenic
virus has become the standard method for oncolytic virus development. Typically,
DNA viruses are used for this strategy.
T‐Vec
T‐Vec is a double‐mutated HSV‐1 with deletions in
the γ34.5 and α47 genes, and the human granulocyte‐macrophage colony‐stimulating factor
(GM‐CSF) gene inserted
into the deleted γ34.5 loci.14 The deletion in the γ34.5 genes
is mainly responsible for cancer‐selective replication and attenuation
of pathogenicity.15, 16, 17 Because the γ34.5 gene
functions to negate the host cell's shut‐off of protein synthesis upon viral
infection,18 inactivation of γ34.5 renders
the virus unable to replicate in normal cells. However, because cancer cells
are in defect of the shut‐off
response, γ34.5‐deficient
HSV‐1 can still replicate
in cancer cells.19 The α47 gene functions
to antagonize the host cell's transporter associated with antigen presentation;
therefore, the deletion of the gene precludes the downregulation of MHC class I
expression, which should enhance the antitumor immune responses.20, 21, 22 The deletion in the α47 gene
also results in immediate early expression of the neighbor US11 gene,
which results in enhanced viral replication in cancer cells.23 The GM‐CSF expression was
intended to enhance the antitumor immunity induction, although convincing
preclinical evidence has not been shown.
The safety of T‐Vec was tested in a
phase I study in patients with various metastatic tumors, including breast, head/neck
and gastrointestinal cancers, and malignant melanoma. Overall, intralesional
administration of the virus was well tolerated by patients.14 Although no complete or partial
responses were observed, stable disease was observed in several patients, and
most tumor biopsies showed tumor necrosis. T‐Vec was further tested in phase II
studies in patients with metastatic melanoma.24 A single arm phase II study
resulted in an overall response rate of 26%, with responses in both injected
and uninjected lesions, including visceral lesions. An increase in CD8+ T cells and a
reduction in CD4+FoxP3+ regulatory T
cells were detected in biopsy samples of regressing lesions.25 A randomized phase III trial was
performed in patients with unresected stage IIIB–IV melanoma (OPTiM; NCT00769704).13 A total of 436 patients were
randomly assigned in a 2:1 ratio to intralesional T‐Vec or subcutaneous
GM‐CSF treatment arms. T‐Vec was administered
at a concentration of 108 plaque forming units (pfu)/mL
injected into 1 or more skin or subcutaneous tumors on Days 1 and 15 of each 28‐day cycle for up to
12 months, while GM‐CSF
was administered at a dose of 125 μg/m²/day subcutaneously for 14 consecutive
days followed by 14 days of rest, in 28‐day treatment cycles for up to 12
months. At the primary analysis, 290 deaths had occurred (T‐Vec, n =
189; GM‐CSF, n =
101). The durable response rate (objective response lasting continuously ≥6
months) was significantly higher in the T‐Vec arm (16.3%) compared with the GM‐CSF arm (2.1%). The
overall response rate was also higher in the T‐Vec arm (26.4 vs 5.7%).
The most common adverse events with T‐Vec were fatigue, chills and pyrexia,
but the only grade 3 or 4 treatment‐related adverse event, occurring in
over 2% of patients, was cellulitis (T‐Vec, n = 6; GM‐CSF, n =
1). There were no fatal treatment‐related adverse events. At the time of
publication, median overall survival (OS) was 23.3 months for the T‐Vec arm versus 18.9
months for the GM‐CSF
arm (hazard ratio, 0.79; P = 0.051),13 but the difference in OS became
significant (P = 0.049) by the time of drug application. The
treatment benefit in OS was more obviously significant when T‐Vec was used as the
first‐line treatment, and
in the subgroup of patients with stage IIIB, IIIC or IVM1.13 This phase III trial was the
first to prove that local intralesional injections with an oncolytic virus can
not only suppress the growth of injected tumors but also prolong the OS,
supposedly via induction of systemic antitumor immunity. Based on this
observation, several clinical trials of T‐Vec in combination with systemic
administration with immune check point inhibitors are ongoing.
G47∆
G47Δ is a triple‐mutated third‐generation oncolytic
HSV‐1 that was developed
by Todo et al. by adding another deletion mutation to the genome of
G207, a second generation HSV‐1.26, 27 G47∆ was developed to strengthen
the antitumor efficacy while retaining the safety features of G207, mainly
through enhancing the capability to elicit specific antitumor immunity.27 Two of the mutations of G47Δ are
created in the γ34.5 and α47 genes, the same genes that
T‐Vec utilizes. G47∆
further has an insertion of the Escherichia coli LacZ gene
inactivating the ICP6 gene. The ICP6 gene
encodes the large subunit of ribonucleotide reductase (RR) that is essential
for viral DNA synthesis.28, 29 When ICP6 is
inactivated, HSV‐1
can replicate only in proliferating cells that express high enough levels of
host RR to compensate for the deficient viral RR. Because of the three manmade
mutations in the genome, G47∆ should be much attenuated and, therefore, safer
in normal tissues than those with two mutations such as G207 and T‐Vec. Furthermore,
because the immediate‐early
expression of US11 caused by the deletion within the α47 gene
prevents the premature termination of protein synthesis that slows the growth
of γ34.5‐deficient
HSV‐1 strains such as
G207, G47∆ shows augmented replication capability in cancer cells, resulting in
having a wider therapeutic window than any other oncolytic HSV‐1.
G47Δ demonstrated a greater replication
capability and a higher antitumor efficacy than G207.27 G47∆ exhibited efficacy in
basically all in vivo solid tumor models tested, including
glioma, breast cancer,30prostate cancer,31, 32, 33 schwannoma,34 nasopharyngeal carcinoma,35 hepatocellular carcinoma,36colorectal cancer,37 malignant peripheral nerve sheath
tumor38 and thyroid carcinoma.39 G47∆ has been shown to kill
cancer stem cells derived from human glioblastoma efficiently.40
G47∆ is currently the only third
generation HSV‐1
to be tested in humans.27, 41 Following the phase I–IIa study
in patients with recurrent glioblastoma that was conducted in Japan and
successfully completed in 2014, a phase II study started in 2015 in patients
with residual or recurrent glioblastoma (UMIN000015995). G47∆ (1 × 109 pfu) is
injected stereotactically into the brain tumor twice within 2 weeks and then
every 4 weeks, for a maximum six times. In February 2016, G47∆ was designated
as a “Sakigake” breakthrough therapy drug by the Ministry of Health, Labour and
Welfare of Japan (MHLW). “Sakigake” is a Japanese word meaning “ahead of the
world.” This new system by the Japanese government provides the designated drug
candidate, namely G47∆, with an early assessment and priority reviews by the
Pharmaceuticals and Medical Devices Agency of Japan (PMDA), and therefore should
allow its fast‐tracked
drug approval by MHLW.
Besides the clinical trials in
glioblastoma, we have just completed a single arm phase I study in patients
with castration‐resistant
prostate cancer, in which 3 × 108 pfu of G47∆ was injected into the
prostate using a transrectal ultrasound‐guided transperineal technique
(UMIN000010463). Dose escalation was planned in three cohorts, with patients
receiving G47∆ twice in the first cohort, three times in the second and four
times in the third. The treatment was well tolerated by patients, with no
severe adverse events attributable to G47∆ observed to date. A phase I study
has been ongoing in patients with recurrent olfactory neuroblastoma since 2013
(UMIN000011636).
JX‐594
JX‐594 (pexastimogene devacirepvec, Pexa‐Vec) is a
genertically engineered vaccinia virus that has a mutation in the TK gene,
conferring cancer cell‐selective
replication, and an insertion of the human GM‐CSF gene, augmenting the antitumor
immune response. JX‐594
also has a LacZ gene insertion as a marker.42, 43, 44 The advantages of using vaccinia
virus include intravenous stability for delivery, strong cytotoxicity and
extensive safety experience as a live vaccine.42 In a phase I study, intralesional
injection of primary or metastatic liver tumors with JX‐594 was generally
well tolerated in the context of JX‐594 replication, GM‐CSF expression and
systemic dissemination. Direct hyperbilirubinemia was the dose‐limiting toxicity.45 High dose JX‐594 was used for a
dose‐escalation phase I
trial to test the feasibility of intravenous delivery.46 A randomized phase II dose‐finding trial was
performed in patients with hepatocellular carcinoma.47 When a low or high dose of JX‐594 was infused, OS
was significantly longer in the high dose arm compared with the low dose arm (n =
14 vs 16, median OS 14.1 vs 6.7 months,
respectively). A phase III trial in patients with advanced stage hepatocellular
carcinoma began enrolling patients in late 2015 (PHOCUS, NCT02562755).
In this trial, JX‐594
(109 pfu) is
administered intralesionally three times bi‐weekly at days 1, 15 and 29, followed
by sorafenib at day 43, whereas, in the control arm, sorafenib begins on Day 1
at 400 mg twice daily.
CG0070
CG0070 is an oncolytic adenovirus
developed by Ramesh et al.48 Ad5 adenovirus was engineered so
that the human E2F‐1
promoter drives the E1A gene, and the human GM‐CSF gene is inserted. E2F‐1 is regulated by the
retinoblastoma tumor suppressor protein (Rb), which is commonly mutated in
bladder cancer, and a loss of Rb binding results in a transcriptionally active
E2F‐1.49
A phase I trial of CG0070 was conducted
in patients with non‐muscle‐invasive bladder
cancer who did not respond to BCG therapy.50 Single or multiple (every 28 days
× 3 and/or weekly six times) dose(s) of up to 3 × 1013 virus particles
(vp) were administered intravesically. No clinically significant serious
adverse events related to treatment were reported, and the most common adverse
events observed were grade 1–2 bladder toxicities, such as dysuria, bladder
pain and frequency.50 The overall response rate was
48.6% (17 of 35), which increased to 63.6% (14 of 22) in the multi‐dose cohort. In the
following randomized phase II/III trial in patients with non‐muscle‐invasive bladder
cancer, 15 patients received CG0070 and 7 control patients received other
standard intravesical therapies (BOND, NCT01438112).
Although there was no apparent difference in the initial CR (8 patients of
CG0070 [53%] vs 4 of control group [57%]), CG0070 treatment
demonstrated a better durable response in a subset of high‐risk patients.51 In a single arm phase III trial
that is underway, patients with BCG‐refractory non‐muscle‐invasive bladder
cancer are given CG0070 intravesically at a dose of 1012 vp weekly for 6
weeks. Patients who achieved a partial or complete response at 6 months after
the first intervention are maintained with the same induction cycle every 6
months (BOND2, NCT02365818).
Naturally occurring oncolytic viruses
The idea of using naturally occurring
viruses for the treatment of cancer was almost abandoned after vigorous
attempts during the 1960s and 1970s because of the lack of means to control
viral pathogenicity at the time. However, the idea was revived along with the
emerging development of genetically engineered viruses, and newly developed
naturally occurring viruses are typically those that are not pathogenic in
humans.
Reolysin
Reoviruses are double‐stranded RNA viruses
that replicate preferentially in transformed cell lines but not in normal
cells.52, 53, 54 In theory, oncolytic properties
of reovirus depend on activated Ras signaling.55, 56Reolysin is the T3D strain of reovirus,
which has been most extensively studied among several serotypes as an
anticancer agent, and is currently the only therapeutic wild‐type reovirus in
clinical development.57
The first phase I trial involved
intralesional administration of Reolysin in patients with advanced solid
tumors.58 The most common treatment‐related adverse
events were nausea (79%), vomiting (58%), erythema at the injection site (42%),
fevers/chills (37%) and transient flu‐like symptoms (32%).58 Further phase I studies
demonstrated the safety and broad anticancer activity of Reolysin in prostate
cancer,59malignant glioma,60 metastatic colorectal cancer,61, 62 multiple myeloma63 and solid cancers.64, 65Multiple phase II studies have
investigated intralesional injection of Reolysin together with local
irradiation for the treatment of refractory or metastatic solid tumors,66 intravenous administration of
Reolysin for metastatic melanoma67 and intravenous administration of
Reolysin in combination with chemotherapy for head and neck cancer or lung
squamous cell carcinoma.68, 69
A randomized double‐blinded phase III
trial has been performed, comparing intravenous Reolysin in combination with
paclitaxel and carboplatin versus chemotherapy alone, in patients with
metastatic and/or recurrent head and neck cancer (NCT01166542).
Patients were treated with intravenous administration of 3 × 1010 tissue culture
infectious dose‐50
(TCID50) of Reolysin on days 1–5 with standard doses of intravenous paclitaxel
and carboplatin on day 1 only every 21 days, versus standard doses of
intravenous paclitaxel and carboplatin alone. According to a report by the
company developing Reolysin, of 165 patients analyzed, 118 patients had
regional head and neck cancer with/without distant metastases and 47 patients
had distant metastases only. In patients with regional cancer, a significant
improvement in OS was observed for the Reolysin group versus the control group
(P = 0.0146).57 The FDA in the USA granted
Reolysin an orphan drug designation for malignant glioma, ovarian cancer and
pancreatic cancer in 2015.
Limitations of oncolytic virus
therapy
A wide variety of oncolytic viruses are
currently under clinical development worldwide, and, as described in this
review, each oncolytic virus carries the characteristics of the parental wild‐type virus, not only
the advantages but also the disadvantages. For example, in regards to oncolytic
HSV‐1, such as T‐Vec and G47∆, because
HSV‐1 spreads from cell
to cell and does not naturally cause viremia, oncolytic HSV‐1 is best
administered intralesionally and may not be well suited for intravenous
delivery. However, as proven by the phase III study of T‐Vec in melanoma
patients at advanced stages,13 local intralesional injections
with oncolytic HSV‐1
can act on remote lesions via induction of systemic antitumor immunity and
prolong survival. It has been shown that expression of GM‐CSF does not augment
the efficacy of oncolytic HSV‐1,
while IL‐12 expression does,
in immunocompetent mouse tumor models.31 Therefore, it is likely that the
systemic effect via antitumor immunity was due to the characteristics of HSV‐1 itself rather than
the effect by GM‐CSF.
One major concern of oncolytic virus
therapy has been that the efficacy may be diminished by the presence of
circulating antibodies.57 Viruses that naturally cause
viremia are likely vulnerable to neutralizing antibodies; therefore, for such
viruses, the antitumor effect of intravenous administration may be limited in
patients who have had previous treatment or vaccination. An unfavorable effect
of circulating antibodies was well documented in a clinical trial using
oncolytic measles virus (MV‐NIS)
in patients with multiple myeloma.70 In this dose escalation study, it
was only after the dosing level reached a very high dose of 1011 TCID50 that
intravenous infusion with MV‐NIS
showed efficacy. In a preclinical study using tumor‐bearing
immunocompetent mice, intravenous treatment with reovirus resulted in regrowth
of tumors 3 weeks after initial tumor growth inhibition, which coincided with
the rise in serum anti‐reovirus
antibody titers.71 Phase I data showed that the
maximum neutralizing anti‐reovirus
antibody titers were reached by day 7 in 12 (36%) of 33 patients and at day 14
in 20 patients (61%).72 It was, therefore, recommended
that, for systemic treatment, reovirus should be administered in rapid,
repeated, high doses within the first week of treatment before the rise of
serum neutralizing antibodies, and that it should be used in combination with
other anticancer therapies.57
Oncolytic virus as immunotherapy
All genetically engineered oncolytic
viruses described in this review were designed to enhance the induction of
antitumor immunity that accompanies the oncolytic activity. Both T‐Vec and G47∆ have a
deletion in the α47 gene, the product of which inhibits the
transporter associated with antigen presentation; therefore, cancer cells
subjected to the oncolytic activities of these viruses are vulnerable to immune
surveillance, and the processing by antigen presenting cells is likely
facilitated.21, 22 A combination with systemic
administration of immune checkpoint inhibitor is a reasonable strategy to
enhance the efficacy of oncolytic viruses. In a preclinical study,
intralesional Reolysin treatment in combination with intravenous anti‐PD‐1 antibody
administration was significantly more efficacious than Reolysin or anti‐PD‐1 alone in mice with
subcutaneous melanoma.73 A phase Ib/II clinical trial of T‐Vec in combination
with ipilimumab (anti–CTLA4) is currently ongoing in patients with stage IIIb‐IV melanoma (NCT01740297).
Preliminary results from the first 18 patients showed that the median time to
response was 5.3 months, and the 18‐month PFS and OS rates were 50% and
67%, respectively, with a median follow‐up of 17 months.74. An open‐label Phase Ib/III study in patients
with previously untreated, unresected stage IIIb–IVM1c melanoma will further
evaluate the safety and efficacy of the combination of T‐Vec and pembrolizumab
(anti–PD‐1) compared with
pembrolizumab alone (NCT02263508).75 A phase I study of T‐Vec in combination
with pembrolizumab has also started for head and neck cancer in late 2015
(Masterkey232, NCT02626000). For all oncolytic virus therapy,
long‐term side effects
from the induction of systemic antitumor immunity, including development of
autoimmune diseases, should be closely investigated.
Like T‐Vec, JX‐594 and CG0070 that have the GM‐CSF gene inserted in
the viral genome, “arming” oncolytic viruses with transgene(s) is a useful
strategy to add certain antitumor functions to oncolytic viruses. According to
preclinical studies with oncolytic HSV‐1, however, GM‐CSF is not exactly an
ideal transgene for “arming”; rather, interleukin 12, interleukin 18 or soluble
B7‐1 would significantly
enhance the antitumor efficacy via augmenting the antitumor immunity induction.31, 32, 76 Besides immunostimulatory genes,
various transgenes of other antitumor functions, including antiangiogenesis,
have been utilized to arm oncolytic viruses.77, 78, 79
Conclusion
It would not be too early to say that
oncolytic virus therapy is now established as an approach to treat cancer.
Because an induction of specific antitumor immunity in the course of oncolytic
activities is the common feature that plays an important role in presenting
antitumor effects, the efficacy of oncolytic virus therapy is expected to
improve further when combined with immunotherapy. By arming oncolytic viruses
with functional transgenes, a whole panel of oncolytic viruses with a variety
of antitumor functions would be available in the future, from which a
combination of appropriate viruses can be chosen according to the type and
stage of cancer. A new era of cancer treatment seems at dawn, where cancer
patients can freely choose oncolytic virus therapy as a treatment option.
Disclosure Statement
Tomoki Todo owns the patent right for
G47∆ in multiple countries including Japan. Tomoki Todo is the principal
investigator of the ongoing phase II clinical trial of G47∆ in glioblastoma
patients in Japan, which is funded by research grants from the MHLW of Japan,
the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of
Japan, and the Japan Agency of Medical Research and Development (AMED).
Acknowledgments
The clinical development of G47Δ is
supported in part by the Translational Research Network Program of the MEXT of
Japan, research grants from the MHLW of Japan and the AMED. G47∆ clinical
trials are supported in part by the Research Hospital, the Institution of
Medical Science, The University of Tokyo, and The University of Tokyo Hospital.
Notes
Cancer Sci 107 (2016)
1373–1379
Notes
Funding Information
Translational Research Network Program
of the MEXT of Japan; Research Grants from MHLW of Japan and the AMED.
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