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1.  Replicating viral vectors for cancer therapy: strategies to synergize with host immune responses 
Microbial biotechnology  2012;5(2):251-259.
Summary
Tumour‐specific replicating (oncolytic) viruses are novel anticancer agents, currently under intense investigation in preclinical studies and phase I–III clinical trials. Until recently, most studies have focused on the direct antitumour properties of these viruses. There is now an increasing body of evidence indicating that host immune responses may be critical to the efficacy of oncolytic virotherapy. Although the immune response to oncolytic viruses can rapidly restrict viral replication, thereby limiting the efficacy of therapy, oncolytic virotherapy also has the potential to induce potent antitumoural immune effectors that destroy those cancer cells, which are not directly lysed by virus. In this review, we discuss the role of the immune system in terms of antiviral and antitumoural responses, as well as strategies to evade or promote these responses in favour of improved therapeutic potentials.
doi:10.1111/j.1751-7915.2011.00296.x
PMCID: PMC3815785  PMID: 21923638
2.  Oncolytic viruses: a novel form of immunotherapy 
Expert review of anticancer therapy  2008;8(10):1581-1588.
Oncolytic viruses are novel anticancer agents, currently under investigation in Phase I–III clinical trials. Until recently, most studies have focused on the direct antitumor properties of these viruses, although there is now an increasing body of evidence that the host immune response may be critical to the efficacy of oncolytic virotherapy. This may be mediated via innate immune effectors, adaptive antiviral immune responses eliminating infected cells or adaptive antitumor immune responses. This report summarizes preclinical and clinical evidence for the importance of immune interactions, which may be finely balanced between viral and tumor elimination. On this basis, oncolytic viruses represent a promising novel immunotherapy strategy, which may be optimally combined with existing therapeutic modalities.
doi:10.1586/14737140.8.10.1581
PMCID: PMC2729453  PMID: 18925850
adaptive; clinical trial; immune response; immunotherapy; innate; oncolytic virus
3.  ONCOLYTIC VIROTHERAPY 
Nature biotechnology  2012;30(7):10.1038/nbt.2287.
Oncolytic virotherapy is an emerging treatment modality which uses replication competent viruses to destroy cancers. Advances in the past two years include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, new strategies to maximize the immunotherapeutic potential of oncolytic virotherapy, and clinical confirmation of a critical viremic thereshold for vascular delivery and intratumoral virus replication. The primary clinical milestone was completion of accrual in a phase III trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Challenges for the field are to select ‘winners’ from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders of magnitude higher yields compared to established vaccine manufacturing processes.
doi:10.1038/nbt.2287
PMCID: PMC3888062  PMID: 22781695
4.  Oncolytic virotherapy in veterinary medicine: current status and future prospects for canine patients 
Oncolytic viruses refer to those that are able to eliminate malignancies by direct targeting and lysis of cancer cells, leaving non-cancerous tissues unharmed. Several oncolytic viruses including adenovirus strains, canine distemper virus and vaccinia virus strains have been used for canine cancer therapy in preclinical studies. However, in contrast to human studies, clinical trials with oncolytic viruses for canine cancer patients have not been reported. An 'ideal' virus has yet to be identified. This review is focused on the prospective use of oncolytic viruses in the treatment of canine tumors - a knowledge that will undoubtedly contribute to the development of oncolytic viral agents for canine cancer therapy in the future.
doi:10.1186/1479-5876-10-3
PMCID: PMC3398296  PMID: 22216938
cancer; canine cancer therapy; oncolytic virus; oncolysis; target molecule, combination therapy
5.  Attenuated oncolytic Measles Virus strains as cancer therapeutics 
Current pharmaceutical biotechnology  2012;13(9):1732-1741.
Attenuated measles virus vaccine strains have emerged as a promising oncolytic vector platform, having shown significant anti-tumor activity against a broad range of malignant neoplasms. Measles virus strains derived from the attenuated Edmonston-B (MV-Edm) vaccine lineage have been shown to selectively infect, replicate in and lyse cancer cells while causing minimal cytopathic effect on normal tissues. This review summarizes the preclinical data that led to the rapid clinical translation of oncolytic measles vaccine strains and provides an overview of early clinical data using this oncolytic platform. Furthermore, novel approaches currently under development to further enhance the oncolytic efficacy of MV-Edm strains, including strategies to circumvent immunity or modulate immune system responses, combinatorial approaches with standard treatment modalities, virus retargeting as well as strategies for in vivo monitoring of viral replication are discussed.
PMCID: PMC3298624  PMID: 21740361
cancer gene therapy; cell carriers; combination therapy; oncolytic measles; tumor targeting; virotherapy
6.  Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice 
Glioblastoma multiforme, one of the most common and aggressive brain tumors in adults, is highly resistant to currently available therapies and often recurs. Due to its poor prognosis and difficult management, there is an urgent need for the development and translation of new anti-glioma therapeutic approaches into the clinic. In this context, oncolytic virotherapy arises as an exciting treatment option for glioma patients. These natural or genetically engineered viruses are able to effectively infect cancer cells, inducing a specific anti-tumor cytotoxic effect. In addition, some viruses have been redesigned to modulate glioma microenvironment, to express cytokines to boost a systemic anti-glioma immune response and to incorporate angiostatic genes to decrease glioma vasculature. Although recent clinical trials have confirmed the safety of oncolytic virotherapies in the brain, their moderate clinical efficacy has not yet matched the encouraging preclinical laboratory results. In this review, we will discuss the leading anti-glioma virotherapy approaches that are presently under preclinical and clinical evaluation. We will also review different delivery methods, in vivo virus behavior, fate, replication, intratumoral spread, activation of anti-tumor immune response, and targeting of glioma stem cells. We will focus on the advantages and limitations of each therapeutic approach and how to overcome these hurdles to effectively translate exciting laboratory results into promising clinical trials.
doi:10.3389/fonc.2013.00032
PMCID: PMC3580888  PMID: 23443138
oncolytic virotherapy; malignant glioma; cancer stem cells; immunomodulation; challenges
7.  Engineered Measles Virus as a Novel Oncolytic Therapy Against Prostate Cancer 
The Prostate  2009;69(1):82-91.
BACKGROUND
No curative therapy is currently available for locally advanced or metastatic prostate cancer. Oncolytic viruses represent a novel class of therapeutic agents that demonstrates no cross-resistance with existing approaches and can therefore be combined with conventional treatment modalities. Measles virus strains deriving from the Edmonston (MV-Edm) vaccine strain have shown considerable oncolytic activity against a variety of solid tumers and hematologic malignancies. In this study, we investigated the antitumor potential of recombinant MV-Edm derivatives as novel oncolytic agents against prostate cancer.
METHODS
The susceptibility of prostate cancer cell lines (PC-3, DU-145, and LNCaP) to measles virus infection was demonstrated using an MV-Edm derivative expressing green fluorescent protein (GFP). MV-Edm replication in prostate cancer cell lines was assessed by one step viral growth curves. The oncolytic effect of an MV-Edm strain engineered to express the human carcinoembryonic antigen (CEA) was demonstrated in vitro by MTT assays and in vivo in subcutaneous PC-3 xenografts. CEA levels were quantitated in cell supernatants and mouse serum samples.
RESULTS
Recombinant MV-Edm strains can effectively infect, replicate in and kill prostate cancer cells. Intratumoral administration of MV-CEA at a total dose of 6 ×106 TCID50 resulted in statistically significant tumor growth delay (P = 0.004) and prolongation of survival (P = 0.001) in a subcutaneous PC-3 xenograft model. Viral growth kinetics paralleled CEA production.
CONCLUSIONS
MV-CEA has potent antitumor activity against prostate cancer cell lines and xenografts. Viral gene expression during treatment can be determined by monitoring of CEA levels in the serum; the latter could allow dose optimization and tailoring of individualized treatment protocols.
doi:10.1002/pros.20857
PMCID: PMC2737678  PMID: 18973133
CEA; measles virus; MV-CEA; prostate cancer; virotherapy
8.  Reovirus modulates autophagy during oncolysis of multiple myeloma 
Autophagy  2013;9(3):413-414.
Multiple myeloma (MM) is a clonal plasma cell malignancy that accounts for 10–15% of newly diagnosed hematological cancers. Although significant advances have been made in the treatment of MM the disease still remains incurable. The oncolytic potential of reovirus has previously been demonstrated by others and us and is currently in phase III clinical trials for solid tumors. In addition a phase I clinical trial has recently been initiated for MM. Despite the clinical activity, the mechanism(s) of cell death caused by reovirus in MM is yet not well elucidated. A comprehensive understanding of reovirus-mediated histology-specific cell death mechanisms is imperative if this therapeutic is to become a standard of care for patients. Previously we have shown that reovirus-mediated cell death of breast and prostate cancer is orchestrated via apoptosis. The present study demonstrates for the first time that in addition to inducing apoptosis reovirus also upregulates autophagy during oncolysis of MM.
doi:10.4161/auto.22867
PMCID: PMC3590261  PMID: 23322106
multiple myeloma; reovirus; autophagy; apoptosis
9.  Oncosuppressive Suicide Gene Virotherapy “PVH1-yCD/5-FC” for Pancreatic Peritoneal Carcinomatosis Treatment: NFκB and Akt/PI3K Involvement 
PLoS ONE  2013;8(8):e70594.
Peritoneal carcinomatosis is common in advanced pancreatic cancer. Despite current standard treatment, patients with this disease until recently were considered incurable. Cancer gene therapy using oncolytic viruses have generated much interest over the past few years. Here, we investigated a new gene directed enzyme prodrug therapy (GDEPT) approach for an oncosuppressive virotherapy strategy using parvovirus H1 (PV-H1) which preferentially replicates and kills malignant cells. Although, PV-H1 is not potent enough to destroy tumors, it represents an attractive vector for cancer gene therapy. We therefore sought to determine whether the suicide gene/prodrug system, yCD/5-FC could be rationally combined to PV-H1 augmenting its intrinsic oncolytic activity for pancreatic cancer prevention and treatment. We showed that the engineered recombinant parvovirus rPVH1-yCD with 5-FC treatment increased significantly the intrinsic cytotoxic effect and resulted in potent induction of apoptosis and tumor growth inhibition in chemosensitive and chemoresistant cells. Additionally, the suicide gene-expressing PV-H1 infection reduced significantly the constitutive activities of NFκB and Akt/PI3K. Combination of their pharmacological inhibitors (MG132 and LY294002) with rPVH1-yCD/5-FC resulted in substantial increase of antitumor activity. In vivo, high and sustained expression of NS1 and yCD was observed in the disseminated tumor nodules and absent in normal tissues. Treatment of mice bearing intraperitoneal pancreatic carcinomatosis with rPVH1-yCD/5-FC resulted in a drastic inhibition of tumor cell spreading and subsequent increase in long-term survival. Together, the presented data show the improved oncolytic activity of wPV-H1 by yCD/5-FC and thus provides valuable effective and promising virotherapy strategy for prevention of tumor recurrence and treatment. In the light of this study, the suicide gene parvovirotherapy approach represents a new weapon in the war against pancreatic cancer. Moreover, these preliminary accomplishments are opening new field for future development of new combined targeted therapies to have a meaningful impact on advanced cancer.
doi:10.1371/journal.pone.0070594
PMCID: PMC3743896  PMID: 23967078
10.  Ex Vivo Infection of Live Tissue with Oncolytic Viruses 
Oncolytic Viruses (OVs) are novel therapeutics that selectively replicate in and kill tumor cells1. Several clinical trials evaluating the effectiveness of a variety of oncolytic platforms including HSV, Reovirus, and Vaccinia OVs as treatment for cancer are currently underway2-5. One key characteristic of oncolytic viruses is that they can be genetically modified to express reporter transgenes which makes it possible to visualize the infection of tissues by microscopy or bio-luminescence imaging6,7. This offers a unique advantage since it is possible to infect tissues from patients ex vivo prior to therapy in order to ascertain the likelihood of successful oncolytic virotherapy8. To this end, it is critical to appropriately sample tissue to compensate for tissue heterogeneity and assess tissue viability, particularly prior to infection9. It is also important to follow viral replication using reporter transgenes if expressed by the oncolytic platform as well as by direct titration of tissues following homogenization in order to discriminate between abortive and productive infection. The object of this protocol is to address these issues and herein describes 1. The sampling and preparation of tumor tissue for cell culture 2. The assessment of tissue viability using the metabolic dye alamar blue 3. Ex vivo infection of cultured tissues with vaccinia virus expressing either GFP or firefly luciferase 4. Detection of transgene expression by fluorescence microscopy or using an In Vivo Imaging System (IVIS) 5. Quantification of virus by plaque assay. This comprehensive method presents several advantages including ease of tissue processing, compensation for tissue heterogeneity, control of tissue viability, and discrimination between abortive infection and bone fide viral replication.
doi:10.3791/2854
PMCID: PMC3197059  PMID: 21730946
11.  PEGylation of Vesicular Stomatitis Virus Extends Virus Persistence in Blood Circulation of Passively Immunized Mice 
Journal of Virology  2013;87(7):3752-3759.
We are developing oncolytic vesicular stomatitis viruses (VSVs) for systemic treatment of multiple myeloma, an incurable malignancy of antibody-secreting plasma cells that are specifically localized in the bone marrow. One of the presumed advantages for using VSV as an oncolytic virus is that human infections are rare and preexisting anti-VSV immunity is typically lacking in cancer patients, which is very important for clinical success. However, our studies show that nonimmune human and mouse serum can neutralize clinical-grade VSV, reducing the titer by up to 4 log units in 60 min. In addition, we show that neutralizing anti-VSV antibodies negate the antitumor efficacy of VSV, a concern for repeat VSV administration. We have investigated the potential use of covalent modification of VSV with polyethylene glycol (PEG) or a function-spacer-lipid (FSL)–PEG construct to inhibit serum neutralization and to limit hepatosplenic sequestration of systemically delivered VSV. We report that in mice passively immunized with neutralizing anti-VSV antibodies, PEGylation of VSV improved the persistence of VSV in the blood circulation, maintaining a more than 1-log-unit increase in VSV genome copies for up to 1 h compared to the genome copy numbers for the non-PEGylated virus, which was mostly cleared within 10 min after intravenous injection. We are currently investigating if this increase in PEGylated VSV circulating half-life can translate to increased virus delivery and better efficacy in mouse models of multiple myeloma.
doi:10.1128/JVI.02832-12
PMCID: PMC3624195  PMID: 23325695
12.  ONCOLYTIC HERPES SIMPLEX VIRUS 1 (HSV-1) VECTORS: INCREASING TREATMENT EFFICACY AND RANGE THROUGH STRATEGIC VIRUS DESIGN 
Drugs of the future  2010;35(3):183-195.
SUMMARY
Viruses have long been considered potential anticancer treatments. Wild-type viruses have been tested as anticancer agents in clinical trials since the 1960s. The possibility of viral oncolysis as an alternate cancer therapy was transformed by the emergence of modern genetic engineering. The herpes simplex virus (HSV) family offers particular advantages for use as a viral oncolytic. The engineered vectors that make up oncolytic HSVs (oHSVs) have demonstrated remarkable safety in clinical trials, with some evidence of efficacy. The past decade has seen a focus on increasing the efficacy of oncolytic vectors by adding exogenous transgenes to enhance tumor destruction. The current paper describes the various strategies for engineering HSV for increased cancer tissue specificity and efficacy. Presented are the rationale, preclinical data and clinical data where available. This is meant to illustrate a basic framework for the development of a novel therapy meant to exploit the viral life cycle for the killing of cancer.
doi:10.1358/dof.2010.35.3.1470166
PMCID: PMC3266817  PMID: 22287818
13.  Potent systemic therapy of Multiple Myeloma utilizing Oncolytic Vesicular stomatitis virus coding for Interferon-beta 
Cancer Gene Therapy  2012;19(7):443-450.
Multiple myeloma (MM) is an incurable malignancy of plasma secreting B-cells disseminated in the bone marrow. Successful utilization of oncolytic virotherapy for myeloma treatment requires a systemically administered virus that selectively destroys disseminated myeloma cells in an immune-competent host. Vesicular stomatitis virus (VSV) expressing Interferon-β (IFNβ) is a promising new oncolytic agent that exploits tumor-associated defects in innate immune signaling pathways to specifically destroy cancer cells. We demonstrate here that a single, intravenous dose of VSV-IFNβ specifically destroys subcutaneous and disseminated 5TGM1 myeloma in an immune competent myeloma model. VSV-IFN treatment significantly prolonged survival in mice bearing orthotopic myeloma. Viral murine IFNβ expression further delayed myeloma progression and significantly enhanced survival compared to VSV expressing human IFNβ. Evaluation of VSV-IFNβ oncolytic activity in human myeloma cell lines and primary patient samples confirmed myeloma specific oncolytic activity but revealed variable susceptibility to VSV-IFNβ oncolysis. The results indicate that VSV-IFNβ is a potent, safe oncolytic agent that can be systemically administered to effectively target and destroy disseminated myeloma in immune competent mice. IFNβ expression improves cancer specificity and enhances VSV therapeutic efficacy against disseminated myeloma. These data show VSV-IFNβ to be a promising vector for further development as a potential therapy for treatment of Multiple myeloma.
doi:10.1038/cgt.2012.14
PMCID: PMC3380174  PMID: 22522623
Oncolytic; virotherapy; myeloma; Vesicular stomatitis virus; systemic
14.  Oncolytic Measles Virus Strains as Novel Anticancer Agents 
Expert opinion on biological therapy  2013;13(4):10.1517/14712598.2013.749851.
Introduction
Replication-competent oncolytic measles virus (MV) strains preferentially infect and destroy a wide variety of cancer tissues. Clinical translation of engineered attenuated MV vaccine derivatives is demonstrating the therapeutic potential and negligible pathogenicity of these strains in humans.
Areas covered
The present review summarizes the mechanisms of MV tumor selectivity and cytopathic activity as well as the current data on the oncolytic efficacy and preclinical testing of MV strains. Investigational strategies to reprogram MV selectivity, escape antiviral immunity and modulate the immune system to enhance viral delivery and tumor oncolysis are also discussed.
Expert Opinion
Clinical viral kinetic data derived from non-invasive monitoring of reporter transgene expression will guide future protocols to enhance oncolytic MV efficacy. Anti-measles immunity is a major challenge of measles-based therapeutics and various strategies are being investigated to modulate immunity. These include the combination of MV therapy with immunosuppressive drugs such as cyclophosphamide, the use of cell carriers and the introduction of immunomodulatory transgenes and wild-type virulence genes. Available MV retargeting technologies can address safety considerations that may arise as more potent oncolytic MV vectors are being developed.
doi:10.1517/14712598.2013.749851
PMCID: PMC3810368  PMID: 23289598
cancer gene therapy; cell carriers; measles virus; MV-NIS; oncolytic virotherapy
15.  Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter for Squamous Cell Cancer of the Head and Neck Radiovirotherapy 
Human Gene Therapy  2011;23(3):295-301.
Abstract
Oncolytic measles virus (MV) encoding the human thyroidal sodium iodide symporter (MV-NIS) has proved to be safe after intraperitoneal or intravenous administration in patients with ovarian cancer or multiple myeloma, respectively, but it has not yet been administered through intratumoral injection in humans. Squamous cell carcinoma (SCC) of the head and neck (SCCHN) usually is locally invasive and spreads to the cervical lymph nodes, which are suitable for the intratumoral administration of oncolytic viruses. To test whether oncolytic MV is an effective treatment for SCCHN, we used oncolytic MV-NIS to infect SCCHN in vitro and in vivo. The data show that SCCHN cells were infected and killed by MV-NIS in vitro. Permissiveness of the tumor cells to MV infection was not affected by irradiation after viral addition. Monitored noninvasively through radioiodine-based single-photon emission computed tomography/computed tomography, intratumorally virus-delivered NIS has concentrated the radioiodine in the MV-NIS–treated tumors in the FaDu mouse xenograft model of human SCCHN, and the antitumor effect could be boosted significantly (p<0.05) either with concomitant cyclophosphamide therapy or with appropriately timed administration of radioiodine 131I. MV-NIS could be a promising new anticancer agent that may substantially enhance the outcomes of standard therapy after intratumoral administration in patients with locally advanced SCCHN.
Li and colleagues investigate the use of oncolytic measles virus encoding human thyroidal sodium iodide symporter (MV-NIS) to treat squamous cell carcinoma of the head and neck (SCCHN) in vitro and in vivo. MV-NIS-treated tumors are able to concentrate administered radioiodine in a mouse xenograft model of human SCCHN, and the antitumor effect is significantly boosted by cyclophosphamide therapy.
doi:10.1089/hum.2011.128
PMCID: PMC3300082  PMID: 22235810
16.  Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeutics 
It is time for those working on oncolytic viruses to take stock of the status of the field. We now have at our disposal an array of potential therapeutic agents, and are beginning to conduct early-phase clinical trials in patients with relapsed/metastatic cancers. By drawing on lessons learned during the development of other biological therapies, such as monoclonal antibodies and targeted small molecule inhibitors, we are now in a position to chart the course of the next wave of trials that will go beyond the phase I studies of safety and feasibility. In this article we review our approach to the development of oncolytic viruses as cancer therapeutics. In doing so, we emphasise the fact that this process is modular and involves multiple iterative steps between the laboratory and the clinic. Ultimately, at least in the medium term, the future of oncolytic virotherapy lies in combination regimens with standard anti-cancer agents such as radiation and chemotherapy.
doi:10.1016/j.cytogfr.2010.02.006
PMCID: PMC3915505  PMID: 20223697
Oncolytic virus; Reovirus; Chemotherapy; Radiotherapy; Clinical trial
17.  Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol 
BMC Cancer  2012;12:99.
Background
The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany.
Methods
ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months.
Discussion
This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies.
Trial registration
ClinicalTrials.gov Identifier: NCT01301430
doi:10.1186/1471-2407-12-99
PMCID: PMC3425127  PMID: 22436661
18.  Phase I Clinical trial of Locoregional Administration of the Oncolytic Adenovirus ONYX-015 in Combination with Mitomycin-C, Doxorubicin, and Cisplatin Chemotherapy in Patients with Advanced Sarcomas 
Summary
Despite many advances in cancer therapy, metastatic disease continues to be incurable in the majority of cancer patients. There is an need for more efficient and less toxic treatments in this setting. Oncolytic virotherapy represents a novel promising direction in the treatment of cancer. Based on preclinical and clinical data, combination with standard chemotherapy has the potential to further increase the antitumor activity of oncolytic virotherapy in a synergistic manner. We present the design of a phase I clinical trial combining intratumoral injections of the oncolytic adenovirus ONYX-015 with systemic chemotherapy in patients with advanced sarcomas.
PMCID: PMC3180922  PMID: 19565928
Cisplatin chemotherapy; doxorubicin; mitomycin-C; oncolytic adenovirus; ONYX-015; sarcomas
19.  Oncolytic virotherapy for pancreatic cancer 
Within the past decade, many oncolytic viruses (OVs) have been studied as potential treatments for pancreatic cancer and some of these are currently under clinical trials. The applicability of certain OVs, such as adenoviruses, herpesviruses and reoviruses, for the treatment of pancreatic cancer has been intensively studied for several years, whereas the applicability of other more recently investigated OVs, such as poxviruses and parvoviruses, is only starting to be determined. At the same time, studies have identified key characteristics of pancreatic cancer biology that provide a better understanding of the important factors or pathways involved in this disease. This review aims to summarise the different replication-competent OVs proposed as therapeutics for pancreatic cancer. It also focuses on the unique biology of these viruses that makes them exciting candidate virotherapies for pancreatic cancer and discusses how they could be genetically manipulated or combined with other drugs to improve their efficacy based on what is currently known about the molecular biology of pancreatic cancer.
doi:10.1017/S1462399411001876
PMCID: PMC3230120  PMID: 21676289
20.  Advances in Oncolytic Virus Therapy for Glioma 
The World Health Organization grossly classifies the various types of astrocytomas using a grade system with grade IV gliomas having the worst prognosis. Oncolytic virus therapy is a novel treatment option for GBM patients. Several patents describe various oncolytic viruses used in preclinical and clinical trials to evaluate safety and efficacy. These viruses are natural or genetically engineered from different viruses such as HSV-1, Adenovirus, Reovirus, and New Castle Disease Virus. While several anecdotal studies have indicated therapeutic advantage, recent clinical trials have revealed the safety of their usage, but demonstration of significant efficacy remains to be established. Oncolytic viruses are being redesigned with an interest in combating the tumor microenvironment in addition to defeating the cancerous cells. Several patents describe the inclusion of tumor microenvironment modulating genes within the viral backbone and in particular those which attack the tumor angiotome. The very innovative approaches being used to improve therapeutic efficacy include: design of viruses which can express cytokines to activate a systemic antitumor immune response, inclusion of angiostatic genes to combat tumor vasculature, and also enzymes capable of digesting tumor extra cellular matrix (ECM) to enhance viral spread through solid tumors. As increasingly more novel viruses are being tested and patented, the future battle against glioma looks promising.
PMCID: PMC2720101  PMID: 19149710
Patent; glioma; astrocytoma; oncolytic virus; HSV-1; adenovirus; reovirus; new castle disease virus; angiogenesis; immune system; extra cellular matrix
21.  Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS 
Oncology Letters  2012;3(5):1159-1165.
Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy. Although new drugs, including bortezomib and lenalidomide, have improved the treatment landscape for MM patients, MM remains incurable. Therefore, screening for novel anti-myeloma drugs is necessary. Gambogic acid (GA), the main active ingredient of gamboges secreted from the Garcinia hanburryi tree, has been reported to exhibit potent anticancer activity in certain solid tumors and hematological malignancies, while there are few studies that are available concerning its effects on MM cells. In the present study, we investigated the anticancer activity of GA on the MM RPMI-8226 cells and further studied the underlying mechanisms by which GA affected the cells. RPMI-8226 cells were cultured and the effect of GA on cell proliferation was analyzed using MTT assay. Hoechst 33258 staining was used to visualize nuclear fragmentation, and reactive oxygen species (ROS) levels were detected. GA was found to have a significant, dose-dependent effect on growth inhibition and apoptosis induction in RPMI-8226 cells. This activity is associated with the accumulation of ROS, which contributes to the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP), accompanied with apoptosis in RPMI-8226 cells treated with GA. Mammalian SIRT1, as the closest homolog of the yeast Sir2, was extensively involved in regulating cell processes, including cell senescence, aging and neuronal protection, as well as having anti-apoptotic properties. Moreover, SIRT1 overexpression has been shown to protect cancer cells from chemotherapy and ionizing radiation. In the present study, we demonstrated that GA has the potential to downregulate the expression of SIRT1 via ROS accumulation. In conclusion, our study found that GA is able to induce apoptosis in RPMI-8226 cells via ROS accumulation followed by caspase-3 activation, PARP cleavage and SIRT1 downregulation. These results suggest that GA may have the potential to not only induce apoptosis in MM cells, but also to decrease the relapse rate of MM.
doi:10.3892/ol.2012.634
PMCID: PMC3389632  PMID: 22783411
gambogic acid; reactive oxygen species; SIRT1; multiple myeloma
22.  Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles 
Viruses  2010;2(1):78-106.
Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.
doi:10.3390/v2010078
PMCID: PMC2883714  PMID: 20543907
oncolytic virus; adenovirus; vaccinia virus; cancer gene; host immune response
23.  Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles 
Viruses  2010;2(1):78-106.
Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.
doi:10.3390/v2010078
PMCID: PMC2883714  PMID: 20543907
oncolytic virus; adenovirus; vaccinia virus; cancer gene; host immune response
24.  Molecular strategies for the treatment of malignant glioma—genes, viruses, and vaccines 
Neurosurgical review  2008;31(2):141-155.
The standard treatment paradigm of surgery, radiation, and chemotherapy for malignant gliomas has only a modest effect on survival. It is well emphasized in the literature that despite aggressive multimodal therapy, most patients survive approximately 1 year after diagnosis, and less than 10% survive beyond 2 years. This dismal prognosis provides the impetus for ongoing investigations in search of improved therapeutics. Standard multimodal therapy has largely reached a plateau in terms of effectiveness, and there is now a growing body of literature on novel molecular approaches for the treatment of malignant gliomas. Gene therapy, oncolytic virotherapy, and immunotherapy are the major investigational approaches that have demonstrated promise in preclinical and early clinical studies. These new molecular technologies each have distinct advantages and limitations, and none has yet demonstrated a significant survival benefit in a phase II or III clinical trial. Molecular approaches may not lead to the discovery of a “magic bullet” for these aggressive tumors, but they may ultimately prove synergistic with more conventional approaches and lead to a broadening of the multimodal approach that is the current standard of care. This review will discuss the scientific background, therapeutic potential, and clinical limitations of these novel strategies with a focus on those that have made it to clinical trials.
doi:10.1007/s10143-008-0121-0
PMCID: PMC3418803  PMID: 18259789
Glioma; Gene therapy; Virotherapy; Oncolytic viruses; Immunotherapy
25.  Targeting Pediatric Cancer Stem Cells with Oncolytic Virotherapy 
Pediatric research  2012;71(4 Pt 2):500-510.
Cancer stem cells (CSC), also termed “cancer initiating cells” or “cancer progenitor cells”, which have the ability to self-renew, proliferate, and maintain the neoplastic clone, have recently been discovered in a wide variety of pediatric tumors. These CSC are thought to be responsible for tumorigenesis, tumor maintenance, aggressiveness and recurrence due to inherent resistance to current treatment modalities such as chemotherapy and radiation. Oncolytic virotherapy offers a novel, targeted approach for eradicating pediatric CSC by utilizing mechanisms of cell killing that differ from conventional therapies. Moreover, oncolytic viruses have the ability to target specific features of CSC such as cell surface proteins, transcription factors, and the CSC microenvironment. Through genetic engineering, a wide variety of foreign genes may be expressed by oncolytic viruses to augment the oncolytic effect. We review the current data regarding the ability of several types of oncolytic viruses (herpes simplex virus-1 (HSV-1), adenovirus, reovirus, Seneca Valley virus, vaccinia virus, Newcastle disease virus, myxoma virus, vesicular stomatitis virus) to target and kill both CSC and tumor cells in pediatric tumors. We highlight advantages and limitations of each virus and potential ways next-generation engineered viruses may target resilient CSC.
doi:10.1038/pr.2011.58
PMCID: PMC3607376  PMID: 22430386

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