Future directions for the field of oncolytic virotherapy: a perspective on the use of vaccinia virus

Oncolytic virotherapy is an emerging biotherapeutic platform based on genetic engineering of viruses capable of selectively infecting and replicating within cancer cells. Such viruses have been found to be both safe and to produce antitumour effects in a number of Phase I and II clinical trials. Early work in this field has been pioneered with strains of adenovirus which, although well suited to gene therapy approaches, have displayed certain limitations in their ability to directly destroy and spread through tumour tissues, particularly after systemic administration. Investigators have subsequently been examining the feasibility of using a variety of different viruses as oncolytic agents. Vaccinia virus is perhaps the most widely administered and successful medical product in history; it displays many of the qualities thought necessary for an effective antitumour agent and is particularly well characterised in people due to its role in the eradication of smallpox. Vaccinia has a short life cycle and rapid spread, strong lytic ability, inherent systemic tumour targeting, a large cloning capacity and well-defined molecular biology. In addition, the virus produces no known disease in humans, has been delivered safely to millions of people and has already demonstrated antitumoural efficacy in trials with vaccine strains. These qualities, along with strategies for further improving the safety and antitumour effectiveness of vaccinia, will be discussed in relation to the broad spectrum of clinical experience already achieved with this virus in cancer therapy.     

Engineering vaccinia virus as an immunotherapeutic battleship to overcome tumor heterogeneity

ABSTRACT

Introduction

Immunotherapy is a rapidly evolving area of cancer therapeutics aimed at driving a systemic immune response to fight cancer. Oncolytic viruses (OVs) are at the cutting-edge of innovation in the immunotherapy field. Successful OV platforms must be effective in reshaping the tumor microenvironment and controlling tumor burden, but also be highly specific to avoid off-target side effects. Large DNA viruses, like vaccinia virus (VACV), have a large coding capacity, enabling the encoding of multiple immunostimulatory transgenes to reshape the tumor immune microenvironment. VACV-based OVs have shown promising results in both pre-clinical and clinical studies, including safe and efficient intravenous delivery to metastatic tumors.     

Systemic virotherapy for multiple myeloma

Introduction: The multiple myeloma (MM) treatment scenario has changed considerably over the past few years. Several novel targeted therapies are currently under consideration including oncolytic virotherapy.

Areas covered: This review provides an analysis of the mechanisms of action of virotherapy, and summarizes the preclinical and clinical studies of systemic virotherapy developed for the treatment of MM. Different types of viruses have been identified, including: adenovirus, vaccinia virus, herpes simplex virus 1, myxoma virus, reovirus, measles virus, vesicular stomatitis virus and coxsackievirus A21.

Expert opinion: The above-mentioned viruses can do more than simply infect and kill malignant plasma cells alone or in combination with chemo and/or radiotherapy. In fact, some of them can also be used to purge myeloma cells from an autologous bone marrow (BM) transplant. Further investigations are required to better explore the best therapeutic combinations for MM and to also overcome antiviral response immunity that can limit the efficacy of this therapeutic strategy.     

Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer

Oncolytic virotherapy is an innovative alternative to more conventional cancer therapies. The ability of some viruses to specifically target and kill malignant cancerous cells while leaving normal tissue unscathed has opened a large repertoire of new and selective cancer killing therapeutic candidates. Poxviruses, such as vaccinia virus, have a long history of use in humans as live vaccines and have more recently been studied as potential platforms for delivery of immunotherapeutics and attenuated variants of vaccinia have been explored as oncolytic candidates. In contrast, the poxvirus myxoma virus is a novel oncolytic candidate that has no history of use in humans directly, as it has a distinct and absolute host species tropism to lagomorphs (rabbits). Myxoma virus has been recently shown to be able to also selectively infect and kill human tumor cells, a unique tropism that is linked to dysregulated intracellular signalling pathways found in the majority of human cancers. This review outlines the existing knowledge on the tropism of myxoma virus for human cancer cells, as well as preclinical data exhibiting its ability to infect and clear tumors in animal models of cancer. This is an exciting new therapeutic option for treating cancer, and myxoma virus joins a growing group of oncolytic virus candidates that are being developed as a new class of cancer therapies in man.     

Oncolytic measles viruses for cancer therapy

New strategies using biological agents are being developed to treat cancer. Live viruses are among these new agents. Virotherapy uses replication-competent viral vectors with strong oncolytic properties. With the use of molecular virology techniques, viruses have been genetically engineered to replicate selectively in tumour cells and are under preclinical and clinical investigation at present. Measles virus (MV) is being used for this purpose. Replication-competent attenuated Edmonston B measles vaccine strain (MV-Edm) is non-pathogenic and has potent antitumour activity against several human tumours. The virus is selectively oncolytic in tumour cells, eliciting extensive cell-to-cell fusion and ultimately leading to cell death. Therefore, MV-Edm is a safe and efficient means to kill tumour cells. Further improvements in existing MV vectors may increase tumour selectivity and oncolytic activity. This review discusses the discovery and development of replication-competent oncolytic MV for cancer therapy.     

Cancer,stem cells,and oncolytic viruses

Cells with stem cell-like attributes, such as self-renewal and pluripotency, have been isolated from hematological malignancies and from several solid tumor types. Tumor-initiating cells, also referred to as cancer stem cells, are thought to be responsible for the initiation and growth of tumors. Like their normal counterparts, putative cancer stem cells show remarkable resistance to radiation and chemotherapy. Their capacity for surviving apparently curative treatment can result in tumor relapse. Novel approaches that target tumor-initiating cells in addition to differentiated malignant cells, which constitute the bulk of the tumor, are required for improved survival of patients with metastatic tumors. Oncolytic viruses enter cells through infection and may therefore be resistant to defense mechanisms exhibited by cancer stem cells. Oncolytic adenoviruses can be engineered to attack tumor stem cells, recognized by linage-specific cell surface markers, dysfunctional stem cell-signaling pathways, or upregulated oncogenic genes. Normal stem cells may possess innate resistance to adenoviruses, as most humans have sustained numerous infections with various wild-type serotypes. This review focuses on current literature in support of cancer stem cells and discusses the possibility of using oncolytic virotherapy for killing these tumor-initiating cells.     

Herpes simplex virus oncolytic vaccine therapy in melanoma

Importance of the field: Advanced melanoma is a devastating disease with a five year survival for Stage IV disease of 10 – 20% and a median survival of 6 – 18 months depending on sub-stage. Current FDA approved therapies demonstrate limited response rates, few complete remissions and no proven survival benefit. New therapies are clearly needed. JSI/34.5-/47-/GM-CSF is a herpes simplex virus-1 (OncoVEX^GM-CSF) oncolytic vaccine therapy designed to induce local and systemic anti-tumor immune responses.

Areas covered in this review: Evolution of current herpes simplex virus oncolytic vaccines from preclinical to clinical studies from 1994 to 2010.

What the reader will gain: Preclinical studies have shown that herpes simplex virus-1 oncolytic vaccines generate local tumor destruction through the lytic action of the virus and local and systemic immune responses. Phase I studies demonstrated limited toxicities with no neurotoxicty. Phase II studies demonstrated durable regressions in patients with metastatic melanoma. A Phase III trial in melanoma is ongoing to determine clinical effectiveness, and a Phase III trial in head and neck cancer will initiate during 2010.

Take home message: JSI/34.5-/47-/GM-CSF is a new generation herpes simplex virus-1 oncolytic vaccine that demonstrates direct tumor lysis and systemic immune responses. Early clinical studies have yielded preliminary evidence of activity.     

Development of targeted oncolytic virotherapeutics through translational research

Background: Oncolytic virotherapeutics is a promising platform for cancer treatment but the product class has yet been successful. The key to success is integration of bidirectional translational research to rapidly address issues encountered in the laboratory and the clinics. Objective: We highlight the hurdles identified for the targeted oncolytic virotherapy approach, specifically those identified in clinical trials with wild-type viruses and first-generation targeted agents. We also analyze the translational research and development that has been applied to overcome these hurdles, including virus engineering and design improvements for next-generation virotherapeutics. Results/conclusion: The iterative loop between the clinic and the lab can function as a major driving force to optimize products from this platform.     

Vaccinia virus and oncolytic virotherapy of cancer

Vaccinia viruses possess many of the key attributes necessary for an ideal viral backbone for use in oncolytic virotherapy. These include a short lifecycle, with rapid cell-to-cell spread. strong lytic ability, a large cloning capacity and well-defined molecular biology. In addition, although capable of replicating in human cells, they are not considered a natural health problem and are especially well characterized. having been delivered to millions of individuals during the campaign to eradicate smallpox. A variety of tumor-targeting mutations have been described in several different vaccinia strains and the expression of a variety of different transgenes has been studied. Early clinical results using either vaccine strains or genetically modified vaccinia strains have demonstrated antitumor effects. Future prospects for the development of these viruses will be discussed.     

Oncolytic measles virus strains as novel anticancer agents

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 noninvasive 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.     

Adenoviral virotherapy for malignant brain tumors

Glioblastoma multiforme is the most common form of primary brain cancer. In the past decade, virotherapy of tumors has gained credence, particularly in glioma management, as these tumors are not completely resectable and tend to micro-metastasize. Adenoviral vectors have an advantage over other viral vectors in that they are relatively non-toxic and do not integrate in the genome. However, the lack of coxsackie and adenovirus receptors on surface of gliomas provides for inefficient transduction of wild-type adenoviral vectors in these tumors. By targeting receptors that are overexpressed in gliomas, modified adenoviral constructs have been shown to efficiently infect glioma cells. In addition, by taking advantage of tumor-specific promoter elements, oncolytic adenoviral vectors offer the promise of selective tumor-specific replication. This dual targeting strategy has enabled specificity in both laboratory and pre-clinical settings. This review examines current trends in adenoviral virotherapy of gliomas, with an emphasis on targeting modalities and future clinical applications.     

Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus

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Talimogene laherparepvec in the treatment of melanoma

Introduction: Metastatic melanoma continues to present a significant therapeutic challenge, with an incidence rate rising faster than that of any other cancer. The last 5 years have seen a revolution in the development of new treatments for advanced melanoma, with oncogene targeted agents and checkpoint inhibitor immunotherapies providing the first convincing evidence of a positive shift in overall survival. The role of oncolytic virotherapy in this rapidly evolving field has long been the subject of debate. However, it is with the development of Talimogene Laheparepvec (T-Vec), an intratumourally administered, genetically modified clinical herpes simplex virus-1 strain that has shown positive results in Phase III testing, that the potential for the use of OV may be realised.

Areas covered: This review will outline some of the recent advances in the treatment of advanced melanoma, with a detailed overview of evidence surrounding the development of T-Vec. A literature search was conducted using the databases ‘Medline’ and ‘Pubmed’, including a subsequent manual search of references to identify papers of further relevance.

Expert opinion: As the pivotal OPTiM trial concludes, we outline some of the potential new directions for T-Vec and OV therapy and evaluate the ever-increasing role these novel agents are likely to play in the future landscape of cancer immunotherapy.     

Fusogenic oncolytic vaccinia virus enhances systemic antitumor immune response by modulating the tumor microenvironment

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Histone modifiers at the crossroads of oncolytic and oncogenic viruses

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Overcoming resistance to oncolytic virus M1 by targeting PI3K-γ in tumor-associated myeloid cells

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Potential and clinical translation of oncolytic measles viruses

Introduction: Oncolytic viruses represent a novel treatment modality that is unencumbered by the standard resistance mechanisms limiting the therapeutic efficacy of conventional antineoplastic agents. Attenuated engineered measles virus strains derived from the Edmonston vaccine lineage have undergone extensive preclinical evaluation with significant antitumor activity observed in a broad range of preclinical tumoral models. These have laid the foundation for several clinical trials in both solid and hematologic malignancies, which have demonstrated safety, biologic activity and the ability to elicit antitumor immune responses.

Areas covered: This review examines the published preclinical data which supported the clinical translation of this therapeutic platform, reviews the available clinical trial data and expands on ongoing phase II testing. It also looks at approaches to optimize clinical applicability and offers future perspectives.

Expert opinion: Reverse genetic engineering has allowed the generation of oncolytic MV strains retargeted to increase viral tumor specificity, or armed with therapeutic and immunomodulatory genes in order to enhance anti-tumor efficacy. Continuous efforts focusing on exploring methods to overcome resistance pathways and determining optimal combinatorial strategies will facilitate further development of this encouraging antitumor strategy.     

Comparison of molecular strategies for breast cancer virotherapy using oncolytic adenovirus

Oncolytic viruses are regulated by the tumor phenotype to replicate and lyse cancer cells selectively. To identify optimal strategies for breast cancer we compared five adenoviruses with distinct regulatory mechanisms: Ad-dl922-947 (targets G1-S checkpoint); Ad-Onyx-015 and Ad-Onyx-017 (target p53/mRNA export); Ad-vKH1 (targets Wnt pathway), and AdEHE2F (targets estrogen receptor/G1-S checkpoint/hypoxic signaling). The quantity of virus required to kill 50% of breast cancer cells after 6 days (EC(50), plaque-forming units per cell) was measured. The most potent virus was Ad-dl922-947 (EC(50), 0.01-5.4 in SkBr3, MDA-231, MDA-468, MCF7, and ZR75.1 cells), followed by wild-type (Ad-WT; EC(50), 0.3-5.5) and AdEHE2F (EC(50), 1.4-3.9). Ad-vKH1 (EC(50), 7.2-72.1), Ad-Onyx-017 (EC(50), 8.4-167), and Ad-Onyx-015 (EC(50), 17.7-377) showed less activity. Most viruses showed limited cytotoxicity in normal human cells, including breast epithelium MCF10A (EC(50), >722) and fibroblasts (EC(50), >192) and only moderate cytotoxicity in normal microvascular endothelial cells (HMVECs; EC(50), 42.8-149), except Ad-dl922-947, which was active in HMVECs (EC(50), 1.6). After injection into MDA-231 xenografts, Ad-WT, AdEHE2F, and Ad-dl922-947 showed replication, assessed by hexon staining and quantitative polymerase chain reaction measurement of viral DNA, and significantly inhibited tumor growth, leading to extended survival. After intravenous injection Ad-dl922-947 showed DNA replication (233% of the injected dose was measured in liver after 3 days) whereas AdEHE2F did not. Overall, AdEHE2F showed the best combination of low toxicity in normal cells and high activity in breast cancer in vitro and in vivo, suggesting that molecular targeting using estrogen response elements, hypoxia response elements, and a dysregulated G1-S checkpoint is a promising strategy for virotherapy of breast cancer.