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At least 19 recordsLinked to original sources
PubMed2004

Future directions: oncolytic viruses.

Oncolytic viruses offer a promising new modality for cancer treatment. The strategy of this therapy is to develop viruses capable of selectively infecting and replicating in malignant tumor cells. Oncolytic viruses can spread and destroy malignant tumors without deleterious effects in normal tissues. These viruses are genetically engineered based on both the biology of replicating viruses and the major genetic defects in human cancer cells, so that they can replicate in cancer cells but not in normal cells. The key to the development of such viruses is the identification of viral genes, the deletion or modification of which enables tumor-specific cell destruction. Several clinical trials have demonstrated the safety of oncolytic viruses as cancer therapy and have also shown some encouraging results. Much evidence suggests that oncolytic viral therapy works in synergy with standard cancer therapies. In this review, we will focus on the oncolytic viruses that may be beneficial to patients with lung cancer in the near future.

Genetic Therapy↗
PubMed2006

Striking out at disseminated metastases: the systemic delivery of oncolytic viruses.

Oncolytic viruses are capable of selective replication in malignant cells and therefore offer levels of potency and specificity that are potentially far higher than conventional treatments for cancer. New developments in vector design and administration regimes are gradually moving toward systemic applications, with the ultimate aim of treating common cancer indications that present with multiple disseminated metastases. Nevertheless, the delivery of therapeutic quantities of viruses via the blood stream to target cells in humans or stringent animal models remains a challenging task: the relatively large size of virus particles restricts their penetration into tissues, and defines their biodistribution and clearance kinetics. In addition, multiple interactions with blood cells and serum proteins can impact on vector bioavailability. Finally, the immunological response to virus administration can vary considerably from patient to patient and even more so between species, making it difficult to draw accurate clinical predictions from model systems. Unfortunately, the extensive experience gained from the application of low-molecular-weight therapeutic drugs provides little insight into the behavior of viral therapeutics administered into the blood stream. In this review, the fate of virus particles following intravenous delivery is described, followed by an assessment of the latest approaches to control and improve vector delivery.

Humans↗
PubMed2007

Virotherapy with a type 2 herpes simplex virus-derived oncolytic virus induces potent antitumor immunity against neuroblastoma.

PURPOSE: We recently constructed an oncolytic virus from type 2 herpes simplex virus (HSV-2) that selectively targets and kills tumor cells with an activated Ras signaling pathway. Designated FusOn-H2, this virus has shown several discrete killing mechanisms. Here, we evaluated the antitumor immune responses after FusOn-H2-mediated virotherapy in a syngeneic murine neuroblastoma model. EXPERIMENTAL DESIGN: We directly injected FusOn-H2 into established tumors and then measured its antitumor effect and the accompanying tumor-specific immune responses. Several oncolytic HSVs constructed from HSV-1 were included in the same experiments for comparisons. RESULTS: Our data show that tumor destruction by FusOn-H2 in vivo induces potent antitumor immune responses in this syngeneic neuroblastoma model. The elicited cellular immunity not only eradicated neuroblastoma cells in vitro but also inhibited the growth of tumors at sites distant from the virus injection site. Moreover, adoptive transfer of splenocytes from mice receiving virotherapy to naïve mice resulted in a measurable antitumor effect. CONCLUSION: We conclude that the ability of FusOn-H2 to induce tumor-specific cellular immunity expands the oncolytic repertoire of this virus and increases the likelihood that its use in patients would produce significant therapeutic benefits.

Animals↗
PubMed2006

Naturally oncolytic viruses.

Naturally oncolytic viruses are replication-competent viruses that have an innate ability to selectively infect and kill tumor cells. Despite being used in the original attempts to treat cancer with live viruses five decades ago, interest in naturally oncolytic viruses has lagged behind the support for engineered adenoviruses and herpesviruses as cancer therapeutics. Recently, however, there has been renewed interest in the high potency and selectivity of these naturally occurring agents. In this review, the mechanism of selectivity as well as the preclinical and clinical activity of naturally oncolytic viruses will be discussed.

Animals↗
PubMed2006

Variable deficiencies in the interferon response enhance susceptibility to vesicular stomatitis virus oncolytic actions in glioblastoma cells but not in normal human glial cells.

With little improvement in the poor prognosis for humans with high-grade glioma brain tumors, alternative therapeutic strategies are needed. As such, selective replication-competent oncolytic viruses may be useful as a potential treatment modality. Here we test the hypothesis that defects in the interferon (IFN) pathway could be exploited to enhance the selective oncolytic profile of vesicular stomatitis virus (VSV) in glioblastoma cells. Two green fluorescent protein-expressing VSV strains, recombinant VSV and the glioma-adapted recombinant VSV-rp30a, were used to study infection of a variety of human glioblastoma cell lines compared to a panel of control cells, including normal human astrocytes, oligodendrocyte precursor cells, and primary explant cultures from human brain tissue. Infection rate, cell viability, viral replication, and IFN-alpha/beta-related gene expression were compared in the absence and presence of IFN-alpha or polyriboinosinic polyribocytidylic acid [poly(I:C)], a synthetic inducer of the IFN-alpha/beta pathway. Both VSV strains caused rapid and total infection and death of all tumor cell lines tested. To a lesser degree, normal cells were also subject to VSV infection. In contrast, IFN-alpha or poly(I:C) completely attenuated the infection of all primary control brain cells, whereas most glioblastoma cell lines treated with IFN-alpha or poly(I:C) showed little or no sign of protection and were killed by VSV. Together, our results demonstrate that activation of the interferon pathway protects normal human brain cells from VSV infection while maintaining the vulnerability of human glioblastoma cells to viral destruction.

Cell Line↗
PubMed2005

Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas.

Myxoma virus, a poxvirus previously considered rabbit specific, can replicate productively in a variety of human tumor cells in culture. The purpose of this study was to determine if there was efficacy or toxicities of this oncolytic virus against experimental models of human malignant gliomas in vitro, in vivo, and ex vivo in malignant glioma specimens. In vitro, the majority of glioma cell lines tested (7 of 8, 87.5%) were fully permissive for myxoma virus replication and killed by infection. In vivo, intracerebral (i.c.) myxoma virus inoculation was well tolerated and produced only minimal focal inflammatory changes at the site of viral inoculation. U87 and U251 orthotopic xenograft models were used to assess myxoma virus efficacy in vivo. A single intratumoral injection of myxoma virus dramatically prolonged median survival compared with treatment with UV-inactivated myxoma virus. Median survival was not reached in myxoma virus-treated groups versus 47.3 days (U87; P = 0.0002) and 50.7 days (U251; P = 0.0027) in UV-inactivated myxoma virus-treated groups. Most myxoma virus-treated animals (12 of 13, 92%) were alive and apparently "cured" when the experiment was finished (>130 days). Interestingly, we found a selective and long-lived myxoma virus infection in gliomas in vivo. This is the first demonstration of the oncolytic activity of myxoma virus in vivo. The nonpathogenic nature of myxoma virus outside of the rabbit host, its capacity to be genetically modified, its ability to produce a long-lived infection in human tumor cells, and the lack of preexisting antibodies in the human population suggest that myxoma virus may be an attractive oncolytic agent against human malignant glioma.

Animals↗
PubMed2002

Biosafety and product release testing issues relevant to replication-competent oncolytic viruses.

Replication competent oncolytic viruses, like other biological products, are at risk from contamination by bacteria, fungi, mycoplasma and viruses that must be eliminated from the final product. This article reviews the regulatory guidance for the manufacture and testing for oncolytic virus products. A testing strategy covering the testing of cell lines, virus banks, virus harvests and purified product is described.

Animals↗
PubMed2002

Armed therapeutic viruses: strategies and challenges to arming oncolytic viruses with therapeutic genes.

Oncolytic viruses are attractive therapeutics for cancer because they selectively amplify, through replication and spread, the input dose of virus in the target tumor. To date, clinical trials have demonstrated marked safety but have not realized their theoretical efficacy potential. In this review, we consider the potential of armed therapeutic viruses, whose lytic potential is enhanced by genetically engineered therapeutic transgene expression from the virus, as potential vehicles to increase the potency of these agents. Several classes of therapeutic genes are outlined, and potential synergies and hurdles to their delivery from replicating viruses are discussed.

Animals↗
PubMed2003

Oncolytic viruses for treatment of malignant brain tumours.

Wild type viruses have been known for decades for their capability to destroy malignant tumour cells upon infection and intracellular replication. Genetic engineering of such viruses was, however, only recently done in an attempt to improve their utility as biological anticancer agents. Wild type or recombinant viruses able to selectively destroy tumour cells while sparing normal tissue are known as oncolytic viruses. Most oncolytic viruses currently investigated in clinical trials are derived from adenovirus (AV) or herpes simplex virus type I (HSVI). More than 300 patients with solid tumours were now treated in clinical trials with oncolytic viruses, and in most cases virus was administered directly into the tumour mass. About 10% of the above patients had recurrent malignant glioma. Total intratumoral doses of up to 2 x 10(12) virus particles were well tolerated, and in general no severe side effects resulted from the clinical use of oncolytic AV and HSVI, either in the brain or in the rest of the body. Encouraging anti-tumoral activity was demonstrated in some types of tumours treated locally with oncolytic viruses, and systemic chemotherapy was found to potentiate the anti-tumour effect of virus mediated oncolysis. In malignant glioma, standard gene therapy approaches employing non-replicating virus vectors failed to demonstrate significant benefit in clinical studies. Therapy with oncolytic viruses seems to hold more promise in early clinical trials than gene therapy with non-replicating virus vectors. However, further major advancements in virus designs, application modalities, and understanding of the interactions of the host's immune system with the virus are clearly needed before oncolytic virus therapy of malignant brain tumours can be introduced to clinical practice.

Adenoviridae↗
PubMed2003

Lymphomas and oncolytic virus therapy.

There are several well-documented cases in medical literature of the remission of leukemias and malignant lymphomas following natural human viral infections. In the hope of being able to reproduce these spontaneous tumor regressions, investigators have studied various viruses with distinct oncolytic properties. The first attempts to treat patients with oncolytic viruses took place > 80 years ago; however, it achieved little success. With modern technologies and current knowledge of viruses and cancer, there is an expectation for the discovery of efficient oncolytic viral therapies. This article will review the current knowledge of oncolytic viruses in relation to the treatment of lymphoma.

Animals↗
PubMed2000

Oncolytic viruses as novel anticancer agents: turning one scourge against another.

Although the use of viruses as oncolytic agents is an historic concept, the use of genetically modified viruses to selectively target tumour cells is relatively novel and recent. The ability of viruses to efficiently infect and lyse cells, combined with the potential augmentation of this effect by progeny viruses throughout the tumour provide justification for exploitation of these agents in cancer therapy. Before application to humans, though, issues related to tumour cell selectivity, lack of toxicity to normal tissues and the effect of the antiviral immune response, will have to be clarified. The more commonly used oncolytic viruses are based on mutant strains of herpes simplex virus, adenovirus and reovirus. The tumour selectivity of each of these strains is discussed, particularly the complementation of the viral defect by cellular pathways involved in tumourigenesis. The combination of oncolytic viruses with radiation, chemotherapy and gene therapy is also reviewed. Further study of the interaction of viral proteins with cellular pathways involved in cell cycle control will provide the rationale for viral mutants with increased selectivity for tumour cells.

Adenoviridae↗
PubMed2003

Oncolytic viruses for the therapy of brain tumors and other solid malignancies: a review.

In spite of significant advances in the understanding of molecular processes in tumor biology that have led to the development of oncologic therapeutic strategies, the prognosis for several types of tumors (such as brain, pancreas, or hepatic malignancies) remains dismal. Without question, a strong need exists for continued investigations in new agents and new therapeutic regimens. The realization that several genes used by viruses in their lytic life cycle interact and/or complement the function of genes employed by cells in cellular events linked to cell cycle progression, apoptosis, and/or metabolism immediately suggests the development of treatment strategies wherein viral mutants could be employed as selective anticancer agents. Such viruses (designated as oncolytic viruses) can selectively grow in tumor cells, produce viral progeny in those cells, lyse them and release this progeny that can then infect additional cells in the tumor mass. A theoretical advantage of oncolytic viruses (OV) is that their numbers should augment within the tumor mass, a property that is lacking with drugs or radiation treatments. Additionally, Ovs' mode of tumor killing differs from standard anticancer agents, providing the possibility for synergistic interactions in multimodal tumor therapies. In this review, we will describe the development of OVs and briefly review the life cycle of their wild-type (wt) counterparts. We will also summarize published results from OV clinical trials and attempt to provide a perspective on research in this area.

Animals↗
PubMed2003

Comparison of replication-selective, oncolytic viruses for the treatment of human cancers.

During the last century, many attempts have been made to explore the cytotoxic effects of several wild-type viruses as oncolytic agents. Until recently, attenuated and replication-defective viruses have been used as vectors for cancer gene therapy for safety purposes. To enhance potency, both approaches have been combined by 'arming' these viruses with therapeutic transgenes. In order to enhance the therapeutic index, several strategies have been evaluated to generate tumor-selective oncolytic viruses, including the use of tumor-specific promoters which transcriptionally target viral genes pivotal for replication, or by deletion of viral functions dispensable for propagation in tumor cells but essential for productive infection of normal cells. In addition, retargeting of the adenoviral tropism towards tumors by capsid or envelope modifications has been evaluated. Controlled clinical trials with an oncolytic adenovirus in combination with chemotherapy have shown encouraging antineoplastic activity. For future vector developments, it will be crucial to achieve maximum vector distribution and transgene expression within tumors, to trigger a specific systemic immune effector response against treated and untreated lesions, and to modulate the immune system to avoid immune-mediated inactivation or destruction of the virus. In the context of replication-competent vectors without approved antiviral agents, suicide genes may be used as a fail-safe mechanism in the case of a runaway infection. Here, the most commonly used oncolytic viruses are reviewed with focus on their unique biological properties as well as the status of several of these mutants in clinical trials.

Animals↗
PubMed2007

Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity.

Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. However, the host immune system remains a significant obstacle to effective systemic administration of virus in a clinical setting. Here, we demonstrate the severe negative impact of the adaptive immune response on the systemic delivery of oncolytic vesicular stomatitis virus (VSV) in an immune-competent murine tumor model, an effect mediated primarily by the neutralization of injected virions by circulating antibodies. We show that this obstacle can be overcome by administering virus within carrier cells that conceal viral antigen during delivery. Infected cells were delivered to tumor beds and released virus to infect malignant cells while sparing normal tissues. Repeated administration of VSV in carrier cells to animals bearing metastatic tumors greatly improved therapeutic efficacy when compared with naked virion injection. Whole-body molecular imaging revealed that carrier cells derived from solid tumors accumulate primarily in the lungs following intravenous injection, whereas leukemic carriers disseminate extensively throughout the body. Furthermore, xenogeneic cells were equally effective at delivering virus as syngeneic cells. These findings emphasize the importance of establishing cell-based delivery platforms in order to maximize the efficacy of oncolytic therapeutics.

Animals↗
PubMed2005

Cyclophosphamide allows for in vivo dose reduction of a potent oncolytic virus.

The success of cancer virotherapy depends on its efficacy versus toxicity profile in human clinical trials. Progress towards clinical trials can be hampered by the relatively elevated doses of oncolytic viruses administered in animal models to achieve an anticancer effect and by the even higher doses required in humans to approximate an animal bioequivalent dose. Such elevated doses of injected viral proteins may also lead to undesirable toxicities and are also very difficult to produce in a biotechnological setting. We report that a relatively potent herpes simplex virus type 1 oncolytic virus (rQNestin34.5) produces 45% survivors at a dose of 3 x 10(4) plaque-forming units (pfu) in a 9-day-old mouse model of human glioma. Unlike our previous findings with less potent oncolytic viruses, though, the preadministration of cyclophosphamide did not enhance this survival or affect oncolytic virus tumor distribution and tumor volume. However, when oncolytic virus doses were reduced (3 x 10(3) and 3 x 10(2) pfu), cyclophosphamide significantly enhanced both animal survival and oncolytic virus tumor distribution and also reduced tumor volumes. These findings thus show that cyclophosphamide allows for dose reduction of doses of a relatively potent oncolytic virus, a finding with implications for the development of clinical trials.

Animals↗
PubMed2002

Oncolytic virus therapy using genetically engineered herpes simplex viruses.

An increasing number of oncolytic virus vectors has been developed lately for cancer therapy. Herpes simplex virus type 1 (HSV-1) vectors are particularly useful, because they can be genetically engineered to replicate and spread highly selectively in tumor cells and can also express multiple foreign transgenes. These vectors can manifest cytopathic effect in a wide variety of tumor types without damaging normal tissues, provide amplified gene delivery within the tumor, and induce specific antitumor immunity. Multiple recombinant HSV-1 vectors have been tested in patients with brain tumors and other cancers, which showed the feasibility of administering replication-competent HSV-1 vectors safely in human organs including the brain. Different approaches are currently undertaken to improve the efficacy of oncolytic HSV-1 therapy which include development of new generation vectors via further genetic engineering of existing safe vectors, combination with immune gene therapy, and combination with conventional therapies. Oncolytic virus therapy is a promising therapeutic modality that awaits establishing as an important treatment option for cancer patients in the near future.

Animals↗
PubMed2005

The potential of oncolytic virus therapy for pancreatic cancer.

The objective of this paper was to review a new category of gene therapy using oncolytic viruses for the treatment of pancreatic cancer. The eligibility and feasibility of oncolytic virus therapy as a novel therapeutic agent against pancreatic cancer are discussed as well as basic research for clinical trials, including a historical perspective and the current status of these novel agents. Even combination therapy, such as surgery with radiation and chemotherapy, has not significantly improved the survival rate of pancreatic cancer. Recently, a clinical trial (phase I and II) using an oncolytic adenovirus, ONYX-015, was completed in patients with pancreatic cancer. The phase II trial yielded beneficial results (tumor reduction or stabilization) in about 50% of the patients. A phase I study of the efficacy of oncolytic herpes viruses, G207, OncoVEX GM-CSF, and 1716 against a variety of tumors has been completed, and G207 is in phase II trials for use against brain tumors. In addition, a phase I trial using the herpesvirus showed good tolerance at all dosages. We discuss the basic scientific principles and current results of the above clinical trials with respect to these oncolytic viruses, and then compare the relative advantages and disadvantages of adenoviruses and herpesviruses as oncolytic agents. We also review the published literature on newly developed oncolytic viruses. The concept of oncolytic therapy has been studied for a century. Recent technological developments have made these oncolytic viruses more tumor-specific by exploiting the tumor cell environments. In addition, these viruses have been reported to increase the immunosusceptibility of the tumor cells, and have been designed to express other genes to increase the susceptibility of tumor cells to other therapeutic agents. Oncolytic virus therapy certainly appears to be a feasible treatment for pancreatic cancer.

Adenoviridae↗