Current Cancer
Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 7, Number 2, March 2007
Contents
Oncolytic Virus Therapy
Guest Editor: Hideki Kasuya
Editorial Pp.
121
Oncolytic Virus Therapy – Foreword
Pp. 123-125
H. Kasuya, S. Takeda, S. Shimoyama, T. Shikano, N. Nomura,
N. Kanazumi, S. Nomoto, H. Sugimoto and A. Nakao
[Abstract]
Oncolytic Viruses: What’s Next? Pp.
127-131
John C. Bell
[Abstract]
From ONYX-015 to Armed Vaccinia Viruses: The Education
and Evolution of Oncolytic Virus Development Pp.
133-139
Anne Moon Crompton and David H. Kirn
[Abstract]
Clinical Trials with Oncolytic Adenovirus in China
Pp. 141-148
Wang Yu and Hu Fang
[Abstract]
Oncolytic Herpes Simplex Virus Type 1 and Host Immune
Responses Pp. 149-155
Hiroshi Fukuhara and Tomoki Todo
[Abstract]
Phase 1 Clinical Experience Using Intravenous Administration
of PV701, an Oncolytic Newcastle Disease Virus Pp.
157-167
Robert M. Lorence, M. Scot Roberts, James D. O’Neil,
William S. Groene, Jeffrey A. Miller, Stephen N. Mueller and
Michael K. Bamat
[Abstract]
Clinical Experiment of Mutant Herpes Simplex Virus
HF10 Therapy for Cancer Pp. 169-174
A. Nakao, S. Takeda, S. Shimoyama, H. Kasuya, H. Kimata,
O. Teshigahara, M. Sawaki, T. Kikumori, Y. Kodera, T. Nagasaka,
F. Goshima, Y. Nishiyama and T. Imai
[Abstract]
HSV-1 Viral Oncolysis and Molecular Imaging with PET
Pp. 175-180
Darshini Kuruppu, Jon D. Dorfman and Kenneth K. Tanabe
[Abstract]
Oncolytic Viruses Driven by Tumor-Specific Promoters
Pp. 181-189
Jayson Hardcastle, Kazuhiko Kurozumi, E. Antonio Chiocca
and Balveen Kaur
[Abstract]
Telomerase-Specific Oncolytic Virotherapy for Human
Cancer with the hTERT Promoter Pp. 191-201
Toshiyoshi Fujiwara, Yasuo Urata and Noriaki Tanaka
[Abstract]
Regulatory Aspects of Oncolytic Virus Products
Pp. 203-208
Teruhide Yamaguchi and Eriko Uchida
[Abstract]
Abstracts
[Back to top]
Editorial
At first, Dr. J. C. Bell states in this issue what we should
now do for the next steps and the directions for the oncolytic
virus therapy of the future. He emphasizes the importance
of embracing the technology accumulated so far, and of using
our understanding of the molecular biology of cancer and viruses
for further breakthroughs. In the new era of oncolytic virus
therapy, the environment is changing from early basic research
to a large number of clinical trials. Actually some of them
have yielded approval of a new drug in China for example.
Oncolytic virus therapy is not a mere dream, with many suffering
patients waiting for relief from cancer. About 10 years ago,
the dramatic debut of G207 and Onyx-015 was a giant step in
the field of cancer drug therapy. In 1996, the oncolytc adenovirus,
Onyx-015, was submitted and filed in the Investigational Drug
Section (IDS), and only 4 years later, in 2000, phase III
trials were initiated. H101 is an added E3-deletion similar
in design to ONXY-015. H101 entered phase III clinical trials
in 2000 in China, and 5 years later, was approved by the Chinese
FDA. It took only 9 years (1996 – 2005) for the oncolytic
adenovirus to be approved as a new drug. This new drug, H101,
mostly showed an anti-cancer effect in combination therapy
with conventional chemotherapy drugs. Sunway Biotech in Shanghai
showed the rate of tumor regression (CR+PR) as follows. H101
with chemotherapy : chemotherapy alone = 78.8% : 39.6% (p
value = 0.000). An adenovirus has strong capacity to cause
inflammation at the spot of injection. This inflammation reflex
of adenovirus can exert a strong effect on among oncolytic
viruses. At present, the immune response caused by an oncolytic
virus seems to be one of the important anti-cancer activities
in the human body.
In this issue, Dr. H. Fukuhara and Dr. T. Todo write about
the issue of host immune mechanism and “armed”
oncolytic HSV-1 vectors using G47?. A host body acquires the
immune response through the change of cell surface viral antigen
(MHC-I), and activated CD-8, NK cells would attack tumor cells
including the oncolytic virus. Thus, the strong inflammation
reflex caused by the oncolytic virus may be beneficial in
triggering the subsequent host immune response. They indicate
that virus “oncolysates” may be useful for cancer
immunotherapy. However, the capacity to induce strong inflammation
might imply a dangerous aspect, should excessive high titer
virus be injected into the venous tract. We must not forget
the tragedy of OTC-gene therapy, which occurred at the University
of Pennsylvania. Systemic injection of oncolytic virus is
another topic in this special issue about Vaccinia virus and
Newcastle disease virus. The capacity for systemic injection
includes the possibility of inhibiting distal micro-metastasis,
and is very important for advanced cancer therapy.
Dr. A. M. Crompton and Dr. D. H. Kirn describe the potential
of Vaccinia virus for systemic injection; and Dr. R. M. Lorence
presents a very interesting phenomenon dealing with the systemic
injection of Newcastle disease virus that is related to the
effect of high repeat doses, and a slower infusion rate for
desensitization. Those technical improvements have numerous
possibilities, and may well be effective for other types of
oncolytic virus as well regarding systemic injection.
We also deal in this issue with HF10 clinical trials in Japan.
HF10 is attenuated herpes simplex virus type-1. We show the
pathological changes, caused by HF10 oncolysis in tissues.
The oncolytic virus itself has a great capacity for tumor
cell lysis as shown in the photographs. In the next step,
we hope to perform combination therapy of HF10 with chemotherapy
drugs or radiation. Some papers have stated that combination
therapy of herpes oncolytic virus was expected to increase
virus replication, consecutive tumor regression and survival
rate in an in vivo model, but other studies mentioned
that both radiation and chemotherapy diminished viral replication.
Comprehension of the time-length of viral replication in a
tumor site is very important for the evaluation of the therapy.
It is a very key to oncolytic viral therapy.
Dr. D. Kuruppu and Dr. K. Tanabe have provided major hints
for the evaluation of viral replication and viral existence
in the tumor site using positron emission tomography (PET)
in their description in this issue of the effectiveness of
PET for the evaluation of oncolytic virus therapy. The injection
of biological agents always carries a safety concern when
the human body is involved. One technical solution is the
use of a tumor selective promoter in order to make a virus
more tumor-selective.
Dr. J. Hardcastle and Dr. B. Kaur describe the characteristics
of each virus that is driven by each kind of tumor specific-promoter.
Most adenoviruses have a mutated E1A gene, while most herpes
viruses are mutated with a γ34.5
gene, that is driven by each tumor-specific promoter. Among
many types of tumor-specific promoters, Dr. T. Fujiwara describes
a very attractive tumor-specific promoter, the telomerase-specific
promoter. Telomerase activation is considered to be a critical
step in carcinogenesis, and its activity correlates closely
with human telomerase reverse transcriptase (hTERT) expression,
and only tumor cells that express telomerase activity would
activate this promoter.
Lastly, Dr. T. Yamaguchi, of the National Institute of Health
Sciences in Japan, describes some of the obstacles that must
be cleared in order to obtain new drug approval.
I believe that all of the articles in this special issue have
very high-level content and include many useful suggestions
for considering the next steps to be taken in the field of
oncolytic virus therapy. Our sincere appreciation and heartfelt
thanks to all the authors and contributors involved in the
publication of this special issue.
Hideki Kasuya, MD, PhD.
Executive Guest Editor
Department of Surgery II,
Nagoya University School of Medicine,
Tsurumai-cho 65, Showa-ku,
Nagoya 466-8550, Japan;
Tel: 81-52-744-2249; Fax: 81-52-744-2255;
E-mail: hidekikasuya@aol.com
[Back to top]
Oncolytic Virus Therapy – Foreword
H. Kasuya, S. Takeda, S. Shimoyama, T. Shikano, N. Nomura,
N. Kanazumi, S. Nomoto, H. Sugimoto and A. Nakao
We are very pleased and proud to be able to publish this special
issue of Current Cancer Drug Targets devoted to oncolytic
virus therapy covering basic and clinical research on adenovirus,
vaccinia virus, herpes virus, and Newcastle disease virus.
In these papers, we welcome the world’s top authorities
in the field who have generously contributed their latest
review articles for exclusive publication in this special
issue. Moreover, this issue also includes a range of opinion
from government drug organizations. Here we simply wish to
bring together the newest knowledge and experience in the
field of cutting-edge oncolytic virus therapy for researchers
and every kind of cancer therapist. The Foreword presents
a historical perspective on the development of oncolytic virus
together with the encouraging results of recent clinical trials
(e.g., H101 has been tested in clinical trial of nearly 250
patients and approved for human use by the Chinese FDA, while
PV701 has been tried in over 110 patients, as described in
our special issue).
[Back to top]
Oncolytic Viruses: What’s Next?
John C. Bell
Cancer is a complex disease that often eludes successful treatment
due to its propensity to evolve or adapt in the face of current
therapeutic regimes. It is reasonable to suggest that sophisticated
therapeutics that can attack cancers in multiple, but targeted
ways, will be necessary in order to improve current success
rates. It is the thesis of this article that Oncolytic Viruses
(OVs), are a new generation of “smart therapeutics”
for cancer with tremendous potential to revolutionize the
management of what has become one of mankind’s scourges.
A number of viruses are being developed around the world for
this purpose (one has already been approved for human use
in China [1]) and I propose that it is now essential to embrace
the technology and use our recent and evolving understanding
of the molecular biology of cancer to fully exploit the oncolytic
virus platform. In the remainder of this article I speculate
on some of the next important steps in OV development and
directions the platform may be headed in the future.
[Back to top]
From ONYX-015 to Armed Vaccinia Viruses: The Education
and Evolution of Oncolytic Virus Development
Anne Moon Crompton and David H. Kirn
The current field of oncolytic virus development has evolved
from, and been educated by, the route adenoviruses have taken
to Phase III development in the United States (Onyx-015) and
commercial approval in China (H101). Clinical development
of these E1B-deleted viruses showed that a staged approach,
from single-agent intratumoral injections to trials testing
intravenous delivery and trials in combination with approved
therapies is judicious and can be successful. Additional oncolytic
products are in development, including andenovirus plus other
promising platforms such as herpes simplex virus, Newcastle
disease virus, reovirus and vaccinia virus. These second-generation
products seek to expand clinical utility beyond the modest
local efficacy of Onyx-015/H101 to potent systemic delivery
and efficacy. Improvement of efficacy in metastatic cancer
will depend not only on enhanced killing of tumor cells, but
also on achieving intravenous delivery and better intratumoral
dissemination. Many viruses inherently replicate preferentially
in tumors, and engineering can increase this therapeutic index
by targeting genetic features of cancers. However, both viruses
and cancer cells have complex biologies. Therefore, research
may reveal that there is not a single predictive factor for
tumor specificity. For example, the Onyx-015 mechanism-of-selectivity
has proved to be complex. Further research regarding pathway
dependence for other oncolytic viruses may also reveal multiple
influences on their tumor tropism.
[Back to top]
Clinical Trials with Oncolytic Adenovirus in China
Wang Yu and Hu Fang
Since the 1990s, oncolytic viruses were utilized to treat
cancer patients from phase I to phase III. Oncolytic virus
development in China has been keeping in step with that in
other countries and even accelerated the process in some fields,
especially in conducting clinical trials. H101 is one kind
of oncolytic adenovirus with E1B-55KD and partial E3 deleted
developed by Shanghai Sunwaybio. From 2000-2004, phase I to
phase III clinical trials for treating head and neck cancer
were conducted in China. Clinical data show that H101 is well
tolerable and has good efficacy when combined with chemotherapy
in some cancer treatment modalities. We review the clinical
results and relative issues of H101 in treating cancer and
discuss approaches and possible improvements for the future.
Information on other oncolytic viruses developing in China
is also provided.
[Back to top]
Oncolytic Herpes Simplex Virus Type 1 and Host Immune
Responses
Hiroshi Fukuhara and Tomoki Todo
The use of oncolytic herpes simplex virus type 1 (HSV-1) is
a promising strategy for cancer treatment. Accumulating evidence
indicates that, aside from the extent of replication capability
within the tumor, the efficacy of an oncolytic HSV-1 depends
on the extent of induction of host antitumor immune responses.
Ways to modify the host immune responses toward viral oncolysis
include expression of immunostimulatory molecules using oncolytic
HSV-1 as a vector and co-administration of reagents that modulate
immune reactions. Viral propagation may be enhanced via temporary
suppression of innate immune responses. Elucidation of the
role of the host immune system in oncolytic HSV-1 therapy
is the key to establishing the approach as a useful clinical
means for cancer treatment.
[Back to top]
Phase 1 Clinical Experience Using Intravenous Administration
of PV701, an Oncolytic Newcastle Disease Virus
Robert M. Lorence, M. Scot Roberts, James D. O’Neil,
William S. Groene, Jeffrey A. Miller, Stephen N. Mueller and
Michael K. Bamat
PV701 is a naturally-attenuated, non-recombinant, oncolytic
strain of Newcastle disease virus that displays preclinical
intravenous (IV) efficacy. PV701 is selective at killing human
cancer cells versus normal human cells based on tumor specific
defects in the interferon (IFN)-mediated antiviral response.
This oncolytic virus displays a broad spectrum of antitumor
activity in vitro and in vivo. Preclinical
models successfully predicted key clinical parameters including
the mechanism of toxicity, two complementary strategies (desensitization
and slow infusion) to reduce toxicity, and the starting dose
for phase 1 trials. In three phase 1 trials of 114 patients
using IV administration of PV701, Wellstat Biologics Corporation
has evaluated the effects of dose, schedule, and infusion
rate for PV701. Three general classes of side effects were
seen: flu-like symptoms; tumor-site-specific adverse events
(AEs); and infusion reactions. The first PV701 dose desensitized
the patient to the side effects of further doses, allowing
a marked increase in the maximum tolerated dose for subsequent
doses compared to the first dose. Tumor responses were first
noted at the higher doses achieved using desensitization.
In the most recent phase 1 trial of 19 patients at Hamilton,
Ontario, that employed desensitization, high repeat doses,
and a slower infusion rate (Hamilton Regimen), there were
six responses (4 major; 2 minor) and a total of six patients
with survival for at least 2 years. In addition, patient tolerability
improved using the Hamilton Regimen compared to IV bolus dosing
used previously. Phase 2 studies of this novel biologic agent
are about to begin.
[Back to top]
Clinical Experiment of Mutant Herpes Simplex Virus
HF10 Therapy for Cancer
A. Nakao, S. Takeda, S. Shimoyama, H. Kasuya, H. Kimata,
O. Teshigahara, M. Sawaki, T. Kikumori, Y. Kodera, T. Nagasaka,
F. Goshima, Y. Nishiyama and T. Imai
We reviewed our clinical trial using mutant herpes simplex
virus “HF10”. We have evaluated the safety and
effect of HF10 against recurrent breast cancer since 2003
and also applied HF10 to non-resectable pancreatic cancer
since 2005.
An oncolytic herpes simplex virus type 1, mutant HF10, has
been isolated and evaluated for anti-tumor efficacy in syngeneic
immunocompetent mouse models. From long time before clinical
trial, we have found that the mutant virus can have remarkable
potential to effectively treat cancer in experimental studies
using animals, and that all of the surviving mice acquire
resistance to rechallenge of the tumor cells. A number of
studies have shown that HF10 is effective and safe for use
in localized or peritoneally disseminated malignant tumors
of non-neuronal origin in animals.
Pilot studies using HF10 have been initiated in patients with
metastatic breast cancer. For each patient, 0.5 ml HF10 diluents
at various doses were injected into test nodule, and 0.5 ml
sterile saline was injected into a second nodule. All patients
were monitored for local and systemic adverse effects, and
the nodules were excised 14 days after viral injection for
histopathological studies. All patients tolerated the clinical
trial well. While no adverse effects occurred, there was cancer
cell death and 30–100% regression histopathologically
in recurrent breast cancer.
As mentioned above, intratumoral injection of mutant herpes
simplex virus HF10 for recurrent metastatic breast cancer
was safe and effective. Also a trial for non-resectable pancreatic
cancer being carried out on the basis of the above result
has proved to be innocuous and has been in progress to assess
the clinical benefit and enhance the potentiality of HF10
against cancer.
[Back to top]
HSV-1 Viral Oncolysis and Molecular Imaging with PET
Darshini Kuruppu, Jon D. Dorfman and Kenneth K. Tanabe
Viral oncolysis, the destruction of cancer cells by replicating
viruses, is a new modality of cancer therapy. This strategy
involves use of viruses that are either genetically engineered
to replicate preferentially in neoplastic cells, or use of
viruses that display innate tropism for neoplastic cells.
These viruses may also be modified to deliver transgenes to
destroy cancer cells. While numerous viruses may be used for
this form of cancer therapy, HSV-1 is an attractive vector
for viral oncolysis due to several characteristics including
its high infectivity, ease of genetic engineering, large transgene
capacity, and the availability of an effective medical treatment
for Herpes simplex virus infections. The HSV-1 viral genome
has been manipulated to generate replication conditional viruses
which target cancer cells. Although these viruses are programmed
to replicate preferentially in cancer cells, there is some
unintended replication in normal cells. Currently, biopsy
is the gold standard for monitoring the therapeutic effects
of viral oncolysis. However, a non-invasive test capable of
serial monitoring of therapy during the treatment period is
required for both preclinical and clinical studies. Positron
emission tomography (PET) using HSV thymidine kinase as the
PET reporter gene offers the desired qualities of a non-invasive
test which can be easily repeated to determine the location
and magnitude of viral replication and tumor lysis. We review
viral oncolysis, focusing on HSV-1 viral oncolysis and therapeutic
monitoring by PET.
[Back to top]
Oncolytic Viruses Driven by Tumor-Specific Promoters
Jayson Hardcastle, Kazuhiko Kurozumi, E. Antonio Chiocca
and Balveen Kaur
Oncolytic viruses can selectively replicate in and lead to
tumor cell lysis with minimal infection/replication potential
in adjoining non-neoplastic tissue. Because of paramount safety
concerns, first-generation oncolytic viruses were designed
to be significantly attenuated in their lytic potential. Results
from recent clinical trials have revealed the safety of this
approach, but have underscored the urgency for design and
testing of more tumor-selective and -potent viruses to realize
the full therapeutic potential of this revolutionary treatment
modality. With the discovery of various molecular/genetic
changes associated with neoplasia, tumor-specific transcriptional
targeting of viral virulence is being tapped to generate tumor-
and tissue-specific variants. This review will focus on the
various strategies exploited to generate viruses whose virulence
is governed by tumor-specific transcriptional events.
[Back to top]
Telomerase-Specific Oncolytic Virotherapy for Human
Cancer with the hTERT Promoter
Toshiyoshi Fujiwara, Yasuo Urata and Noriaki Tanaka
Replication-selective tumor-specific viruses present a novel
approach for treatment of neoplastic disease. These vectors
are designed to induce virus-mediated lysis of tumor cells
after selective viral propagation within the tumor. For targeting
cancer cells, there is a need for tissue- or cell-specific
promoters that can express in diverse tumor types and are
silent in normal cells. Recent advances in molecular biology
have fostered remarkable insights into the molecular basis
of neoplasm. Telomerase activation is considered to be a critical
step in carcinogenesis and its activity correlates closely
with human telomerase reverse transcriptase (hTERT) expression.
Since only tumor cells that express telomerase activity would
activate this promoter, the hTERT proximal promoter allows
for preferential expression of viral genes in tumor cells,
leading to selective viral replication. We constructed an
attenuated adenovirus 5 vector (Telomelysin, OBP-301), in
which the hTERT promoter element drives expression of E1A
and E1B genes linked with an internal ribosome entry site
(IRES). Telomelysin replicated efficiently and induced marked
cell killing in a panel of human cancer cell lines, whereas
replication as well as cytotoxicity was highly attenuated
in normal human cells lacking telomerase activity. Thus, the
hTERT promoter confers competence for selective replication
of Telomelysin in human cancer cells, an outcome that has
important implications for the treatment of human cancers.
This article reviews recent findings in this rapidly evolving
field: cancer therapeutic and cancer diagnostic approaches
using the hTERT promoter.
[Back to top]
Regulatory Aspects of Oncolytic Virus Products
Teruhide Yamaguchi and Eriko Uchida
Many types of oncolytic viruses, wild-type virus, attenuated
viruses and genetically-modified viruses, have been developed
as an innovative cancer therapy. The strategies, nature, and
technologies of oncolytic virus products are different from
the conventional gene therapy products or cancer therapy products.
From the regulatory aspects to ensure the safety, efficacy
and quality of oncolytic viruses, there are several major
points during the development, manufacturing, characterization,
non-clinical study and clinical study of oncolytic viruses.
The major issues include 1) virus design (wild-type, attenuated,
and genetically engineered strains), 2) poof of concept in
development of oncolytic virus products, 3) selectivity of
oncolytic virus replication and targeting to cancer cells,
4) relevant animal models in non-clinical studies, 5) clinical
safety, 6) evaluation of virus shedding. Until now, the accumulation
of the information about oncolytic viruses is not enough,
it may require the unique approach to ensure the safety and
the development of new technology to characterize oncolytic
viruses.
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