Special Issue "Oncolytic Virotherapy"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2018)

Special Issue Editor

Guest Editor
Dr. Hiroaki Wakimoto

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02215, USA
Website | E-Mail
Interests: neuro-oncology; glioblastoma; meningioma; oncolytic virus; herpes simplex virus; gene therapy

Special Issue Information

Dear Colleagues,

Oncolytic viruses (OV) are either genetically-engineered or naturally-occurring viruses that exploit defective anti-viral immune response in cancer cells for therapeutic gain. OV selectively replicate and destroy neoplastic cells, while sparing normal cells, leading to release of tumor antigens and induction of adaptive anti-tumor cellular immune response, which is now considered a critical mechanism-of-action (MOA). The multipronged MOA is indeed unique for OV and attributable to both potentially durable response and activity for otherwise refractory anti-apoptotic cancer.

After decades of early developmental stage of OV, the field has finally entered an exciting time; in late 2015 talimogene laherparepvec became the first FDA-approved OV for the treatment of advanced melanoma. Subsequent clinical trial testing talimogene laherparepvec and immune checkpoint inhibitor is reported to show clinical benefits of combining the two modalities in metastatic melanoma patients. These milestones are boosting extensive efforts from both academia and industry to develop OVs from a number of different virus families with the tangible goal to commercialize them as new cancer drugs.

There, perhaps, has never been a better time for us to ponder how to best harness preclinical research to meaningfully advance the field of OV. Clinically relevant questions still abound; selection of virus species for a particular patient or cancer type, modification of immune response against virus and tumor to maximize potency, optimization of delivery and dosing schedule for a given OV, use of appropriate animal model, etc. Laboratory research should be able to approach to some if not all to provide scientific basis and rationales to guide designing clinical trials that have increased likelihood of success. This Special Issue will discuss the cutting-edge research of OV, with a particular emphasis on the role that bench and animal model investigations could play towards ultimately improving management of cancer.

Dr. Hiroaki Wakimoto
Guest Editor

Manuscript Submission Information

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Published Papers (15 papers)

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Research

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Open AccessArticle Rodents Versus Pig Model for Assessing the Performance of Serotype Chimeric Ad5/3 Oncolytic Adenoviruses
Cancers 2019, 11(2), 198; https://doi.org/10.3390/cancers11020198
Received: 15 December 2018 / Revised: 1 February 2019 / Accepted: 6 February 2019 / Published: 8 February 2019
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Abstract
Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor [...] Read more.
Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor (Coxsackie and Adenovirus Receptor, CAR) on cancer cells. Engineering serotype chimeric vectors (Ad5/3) to utilize Adenovirus type 3 (Ad3) receptors has greatly improved their oncolytic potential. Clinical translation of these infectivity-enhanced vectors has been challenging due to a lack of replication permissive animal models. In this study, we explored pigs as a model to study the performance of fiber-modified Ad5/3 chimeric vectors. As a control, the Ad5 fiber-unmodified virus was used. We analyzed binding, gene transfer, replication, and cytolytic ability of Ad5 and Ad5/3 in various non-human cell lines (murine, hamster, canine, porcine). Among all tested cell lines only porcine cells supported active binding and replication of Ad5/3. Syrian hamster cells supported Ad5 replication but showed no evidence of productive viral replication after infection with Ad5/3 vectors. Transduction and replication ability of Ad5/3 in porcine cells outperformed Ad5, a phenomenon often observed in human cancer cell lines. Replication of Ad5 and Ad5/3 was subsequently evaluated in vivo in immunocompetent pigs. Quantitative PCR analyses 7 days post infection revealed Ad5 and Ad5/3 DNA and replication-dependent luciferase activity in the swine lungs and spleen indicating active replication in these tissues. These studies demonstrated the flaws in using Syrian hamsters for testing serotype chimeric Ad5/3 vectors. This is the first report to validate the pig as a valuable model for preclinical testing of oncolytic adenoviruses utilizing Adenovirus type 3 receptors. We hope that these data will help to foster the clinical translation of oncolytic adenoviruses including those with Ad3 retargeted tropism. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessArticle Vaccinia Virus Shuffling: deVV5, a Novel Chimeric Poxvirus with Improved Oncolytic Potency
Cancers 2018, 10(7), 231; https://doi.org/10.3390/cancers10070231
Received: 2 May 2018 / Revised: 31 May 2018 / Accepted: 1 June 2018 / Published: 10 July 2018
Cited by 3 | PDF Full-text (1749 KB) | HTML Full-text | XML Full-text
Abstract
Oncolytic virus (OV) therapy has emerged as a promising approach for cancer treatment with the potential to be less toxic and more efficient than classic cancer therapies. Various types of OVs in clinical development, including Vaccinia virus (VACV)-derived OVs, have shown good safety [...] Read more.
Oncolytic virus (OV) therapy has emerged as a promising approach for cancer treatment with the potential to be less toxic and more efficient than classic cancer therapies. Various types of OVs in clinical development, including Vaccinia virus (VACV)-derived OVs, have shown good safety profiles, but limited therapeutic efficacy as monotherapy in some cancer models. Many different methods have been employed to improve the oncolytic potency of OVs. In this study, we used a directed evolution process, pooling different strains of VACV, including Copenhagen, Western Reserve and Wyeth strains and the attenuated modified vaccinia virus Ankara (MVA), to generate a new recombinant poxvirus with increased oncolytic properties. Through selective pressure, a chimeric VACV, deVV5, with increased cancer cell killing capacity and tumor selectivity in vitro was derived. The chimeric viral genome contains sequences of all parental strains. To further improve the tumor selectivity and anti-tumor activity of deVV5, we generated a thymidine kinase (TK)-deleted chimeric virus armed with the suicide gene FCU1. This TK-deleted virus, deVV5-fcu1 replicated efficiently in human tumor cells, and was notably attenuated in normal primary cells. These studies demonstrate the potential of directed evolution as an efficient way to generate recombinant poxviruses with increased oncolytic potency, and with high therapeutic index to improve cancer therapy. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessArticle Oncolytic Reovirus and Immune Checkpoint Inhibition as a Novel Immunotherapeutic Strategy for Breast Cancer
Cancers 2018, 10(6), 205; https://doi.org/10.3390/cancers10060205
Received: 17 May 2018 / Revised: 8 June 2018 / Accepted: 8 June 2018 / Published: 15 June 2018
Cited by 4 | PDF Full-text (2686 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus [...] Read more.
As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus (RV) for the treatment of breast cancer (BrCa). In vitro, oncolysis and cytokine production were assessed in human and murine BrCa cell lines following RV exposure. Furthermore, RV-induced upregulation of tumor cell PD-L1 was evaluated. In vivo, the immunocompetent, syngeneic EMT6 murine model of BrCa was employed to determine therapeutic and tumor-specific immune responses following treatment with RV, anti-PD-1 antibodies or in combination. RV-mediated oncolysis and cytokine production were observed following BrCa cell infection and RV upregulated tumor cell expression of PD-L1. In vivo, RV monotherapy significantly reduced disease burden and enhanced survival in treated mice, and was further enhanced by PD-1 blockade. RV therapy increased the number of intratumoral regulatory T cells, which was reversed by the addition of PD-1 blockade. Finally, dual treatment led to the generation of a systemic adaptive anti-tumor immune response evidenced by an increase in tumor-specific IFN-γ producing CD8+ T cells, and immunity from tumor re-challenge. The combination of PD-1 blockade and RV appears to be an efficacious immunotherapeutic strategy for the treatment of BrCa, and warrants further investigation in early-phase clinical trials. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessArticle Loss of Cyclin-Dependent Kinase Inhibitor Alters Oncolytic Adenovirus Replication and Promotes More Efficient Virus Production
Cancers 2018, 10(6), 202; https://doi.org/10.3390/cancers10060202
Received: 10 May 2018 / Revised: 6 June 2018 / Accepted: 11 June 2018 / Published: 15 June 2018
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Abstract
We elucidate the role of p21/Waf-1, a cyclin-dependent kinase inhibitor, on the oncolytic infection and replication cycle of adenovirus by studying both mRNA and adenoviral proteins expression. We found that infection in the absence of p21 causes a significant increase in adenoviral genomes [...] Read more.
We elucidate the role of p21/Waf-1, a cyclin-dependent kinase inhibitor, on the oncolytic infection and replication cycle of adenovirus by studying both mRNA and adenoviral proteins expression. We found that infection in the absence of p21 causes a significant increase in adenoviral genomes and late gene expression. Similarly, the oncolytic adenoviral infected p21−/− cells have earlier formation of replication foci and robust replication kinetics that were not observed in the wild type p21/Waf-1 intact cells. These findings suggest a culmination that the presence of intact p21 in host cells causes defects in the oncolytic viral life cycle which results in the production of immature and noninfectious particles. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessArticle Regulation of Constitutive Interferon-Stimulated Genes (Isgs) in Tumor Cells Contributes to Enhanced Antitumor Response of Newcastle Disease Virus-Infected Tumor Vaccines
Cancers 2018, 10(6), 186; https://doi.org/10.3390/cancers10060186
Received: 9 May 2018 / Revised: 29 May 2018 / Accepted: 29 May 2018 / Published: 6 June 2018
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Abstract
Newcastle disease virus (NDV) is an oncolytic virus. As immunogenicity of tumor cells is enhanced by NDV infection, recombinant NDV-infected tumor vaccines (rNDV-TV) are effective methods for inducing specific immunity. However, several tumor cells resist NDV infection, and tumor specific immunity is not [...] Read more.
Newcastle disease virus (NDV) is an oncolytic virus. As immunogenicity of tumor cells is enhanced by NDV infection, recombinant NDV-infected tumor vaccines (rNDV-TV) are effective methods for inducing specific immunity. However, several tumor cells resist NDV infection, and tumor specific immunity is not sufficiently induced by rNDV-TV. Therefore, we clarified the factor contributing to the suppression of NDV infection and attempted to improve rNDV-TV. Initially we investigated the correlation between the NDV infection rate and interferon-related gene expression in six murine tumor cell lines. A significant negative correlation was observed between the constitutive gene expression of Interferon-stimulated genes (ISGs) and NDV infectivity. The NDV infection rate was examined in each tumor cell treated with the Janus kinase (JAK) inhibitor ruxolitinib (Rux). Furthermore, we evaluated the Th1 response induction by Rux-treated rNDV-TV (rNDV-TV-Rux). In Rux-treated tumor cells, Oasl2 gene expression was significantly decreased and viral infectivity was increased. In immunized mice, the number of CD8+ cells, and those expressing the IFN-γ gene, were significantly increased as compared with Rux-untreated rNDV-TV. The infectivity of the virus was dependent on the degree of ISGs expression in tumor cells. To remedy for this problem, rNDV-TV-Rux was expected to have a Th1 immune response. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessArticle A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
Cancers 2018, 10(6), 160; https://doi.org/10.3390/cancers10060160
Received: 20 April 2018 / Revised: 16 May 2018 / Accepted: 17 May 2018 / Published: 25 May 2018
Cited by 7 | PDF Full-text (1183 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessArticle Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro
Cancers 2018, 10(5), 144; https://doi.org/10.3390/cancers10050144
Received: 17 April 2018 / Revised: 2 May 2018 / Accepted: 15 May 2018 / Published: 17 May 2018
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Abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd)-based mono-therapeutic clinical trials have resulted in modest outcomes. [...] Read more.
Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd)-based mono-therapeutic clinical trials have resulted in modest outcomes. The OAd potency could be increased by chemotherapy-induced autophagy, an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. In this study, the ability of alkylating agent temozolomide (TMZ)-induced autophagy to increase OAd replication and oncolysis in TNBC cells was evaluated. Human TNBC MDA-MB-231 and HCC1937 cells and mouse 4T1 cells were infected with an OAd expressing the red fluorescent protein mCherry on the virus capsid (OAdmCherry) alone or in combination with TMZ. TNBC cells treated with OAdmCherry/TMZ displayed greater mCherry and adenovirus (Ad) early region 1A (E1A) expression and enhanced cancer-cell killing compared to OAdmCherry or TMZ alone. The combined therapy-mediated cell death was associated with virus replication and accumulation of the autophagy marker light chain 3 (LC3)-II. Overall, this study provides experimental evidence of TMZ’s ability to increase oncolytic virotherapy in both human and murine TNBC cells. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessFeature PaperArticle Proteomic Analysis of Secretomes of Oncolytic Herpes Simplex Virus-Infected Squamous Cell Carcinoma Cells
Received: 1 December 2017 / Revised: 3 January 2018 / Accepted: 15 January 2018 / Published: 23 January 2018
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Abstract
Oncolytic herpes simplex virus type 1 (HSV-1) strain RH2 induced immunogenic cell death (ICD) with the release and surface exposure of damage-associated molecular patterns (DAMPs) in squamous cell carcinoma (SCC) SCCVII cells. The supernatants of RH2-infected SCCVII cells also exhibited antitumor ability by [...] Read more.
Oncolytic herpes simplex virus type 1 (HSV-1) strain RH2 induced immunogenic cell death (ICD) with the release and surface exposure of damage-associated molecular patterns (DAMPs) in squamous cell carcinoma (SCC) SCCVII cells. The supernatants of RH2-infected SCCVII cells also exhibited antitumor ability by intratumoral administration in SCCVII tumor-bearing mice. The supernatants of RH2-infected cells and mock-infected cells were concentrated to produce Med24 and MedC for proteomic analyses. In Med24, the up- and down-regulated proteins were observed. Proteins including filamin, tubulin, t-complex protein 1 (TCP-1), and heat shock proteins (HSPs), were up-regulated, while extracellular matrix (ECM) proteins were markedly down-regulated. Viral proteins were detected in Med 24. These results indicate that HSV-1 RH2 infection increases the release of danger signal proteins and viral gene products, but decreases the release of ECM components. These changes may alter the tumor microenvironment (TME) and contribute to enhancement of anti-tumor immunity against SCC. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Review

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Open AccessReview The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers
Cancers 2018, 10(10), 356; https://doi.org/10.3390/cancers10100356
Received: 18 July 2018 / Revised: 10 September 2018 / Accepted: 11 September 2018 / Published: 26 September 2018
Cited by 2 | PDF Full-text (306 KB) | HTML Full-text | XML Full-text
Abstract
Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 [...] Read more.
Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev—C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessReview Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors
Cancers 2018, 10(7), 226; https://doi.org/10.3390/cancers10070226
Received: 28 June 2018 / Accepted: 4 July 2018 / Published: 9 July 2018
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Abstract
In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of [...] Read more.
In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In this review, we summarize the OVs evaluated in different types of PBTs, mostly in pre-clinical studies, and we discuss the possible future direction of research in this field. In this sense, one important aspect of OVs antitumoral effect is the stimulation of an immune response against the tumor which is necessary for a complete response in preclinical immunocompetent models and in the clinic. The role of the immune system in the response of OVs needs to be evaluated in PBTs and represents an experimental challenge due to the limited immunocompetent models of these diseases available for pre-clinical research. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessReview Fusogenic Viruses in Oncolytic Immunotherapy
Cancers 2018, 10(7), 216; https://doi.org/10.3390/cancers10070216
Received: 4 June 2018 / Revised: 22 June 2018 / Accepted: 23 June 2018 / Published: 26 June 2018
Cited by 1 | PDF Full-text (644 KB) | HTML Full-text | XML Full-text
Abstract
Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune [...] Read more.
Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune responses directed against the tumor, make oncolytic viruses highly attractive candidates for immunotherapy. Increasing evidence indicates that a subclass of oncolytic viruses, which encodes for fusion proteins, could outperform non-fusogenic viruses, both in their direct oncolytic potential, as well as their immune-stimulatory properties. Tumor cell infection with these viruses leads to characteristic syncytia formation and cell death due to fusion, as infected cells become fused with neighboring cells, which promotes intratumoral spread of the infection and releases additional immunogenic signals. In this review, we discuss the potential of fusogenic oncolytic viruses as optimal candidates to enhance immunotherapy and initiate broad antitumor responses. We provide an overview of the cytopathic mechanism of syncytia formation through viral-mediated expression of fusion proteins, either endogenous or engineered, and their benefits for cancer therapy. Growing evidence indicates that fusogenicity could be an important feature to consider in the design of optimal oncolytic virus platforms for combinatorial oncolytic immunotherapy. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessReview Designer Oncolytic Adenovirus: Coming of Age
Cancers 2018, 10(6), 201; https://doi.org/10.3390/cancers10060201
Received: 20 May 2018 / Revised: 6 June 2018 / Accepted: 11 June 2018 / Published: 14 June 2018
Cited by 6 | PDF Full-text (4806 KB) | HTML Full-text | XML Full-text
Abstract
The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with [...] Read more.
The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessReview Oncolytic Viruses for Multiple Myeloma Therapy
Cancers 2018, 10(6), 198; https://doi.org/10.3390/cancers10060198
Received: 3 May 2018 / Revised: 31 May 2018 / Accepted: 12 June 2018 / Published: 14 June 2018
Cited by 1 | PDF Full-text (961 KB) | HTML Full-text | XML Full-text
Abstract
Although recent treatment advances have improved outcomes for patients with multiple myeloma (MM), the disease frequently becomes refractory to current therapies. MM thus remains incurable for most patients and new therapies are urgently needed. Oncolytic viruses are a promising new class of therapeutics [...] Read more.
Although recent treatment advances have improved outcomes for patients with multiple myeloma (MM), the disease frequently becomes refractory to current therapies. MM thus remains incurable for most patients and new therapies are urgently needed. Oncolytic viruses are a promising new class of therapeutics that provide tumor-targeted therapy by specifically infecting and replicating within cancerous cells. Oncolytic therapy yields results from both direct killing of malignant cells and induction of an anti-tumor immune response. In this review, we will describe oncolytic viruses that are being tested for MM therapy with a focus on those agents that have advanced into clinical trials. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessReview Tune Up In Situ Autovaccination against Solid Tumors with Oncolytic Viruses
Cancers 2018, 10(6), 171; https://doi.org/10.3390/cancers10060171
Received: 26 April 2018 / Revised: 17 May 2018 / Accepted: 29 May 2018 / Published: 31 May 2018
Cited by 1 | PDF Full-text (626 KB) | HTML Full-text | XML Full-text
Abstract
With the progress of immunotherapy in cancer, oncolytic viruses (OVs) have attracted more and more attention during the past decade. Due to their cancer-selective and immunogenic properties, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy [...] Read more.
With the progress of immunotherapy in cancer, oncolytic viruses (OVs) have attracted more and more attention during the past decade. Due to their cancer-selective and immunogenic properties, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. The main challenge in OV approaches is how to redirect the host immunity from anti-virus to anti-tumor and optimize the clinical outcome of cancer patients. Here, we summarize the conceptual updates on oncolytic virotherapy and immunotherapy in cancer, and the development of strategies to enhance the virus-mediated anti-tumor immune response, including: (1) arm OVs with cytokines to modulate innate and adaptive immunity; (2) combining OVs with immune checkpoint inhibitors to release T cell inhibition; (3) combining OVs with immune co-stimulators to enhance T cell activation. Future studies need to be enforced on developing strategies to augment the systemic effect on metastasized tumors. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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Open AccessReview Oncolytic Virotherapy versus Cancer Stem Cells: A Review of Approaches and Mechanisms
Cancers 2018, 10(4), 124; https://doi.org/10.3390/cancers10040124
Received: 16 March 2018 / Revised: 11 April 2018 / Accepted: 14 April 2018 / Published: 19 April 2018
Cited by 2 | PDF Full-text (1180 KB) | HTML Full-text | XML Full-text
Abstract
A growing body of evidence suggests that a subset of cells within tumors are resistant to conventional treatment modalities and may be responsible for disease recurrence. These cells are called cancer stem cells (CSC), which share properties with normal stem cells including self-renewal, [...] Read more.
A growing body of evidence suggests that a subset of cells within tumors are resistant to conventional treatment modalities and may be responsible for disease recurrence. These cells are called cancer stem cells (CSC), which share properties with normal stem cells including self-renewal, pluripotency, drug resistance, and the ability to maintain quiescence. While most conventional therapies can efficiently destroy rapidly dividing cancer cells comprising the bulk of a tumor, they often fail to kill the less abundant and quiescent CSCs. Furthermore, killing of only differentiated cells in the tumor may actually allow for enrichment of CSCs and thereby portend a bad prognosis. Therefore, targeting of CSCs is important to achieve long-term success in cancer therapy. Oncolytic viruses represent a completely different class of therapeutics that can kill cancer cells in a variety of ways, which differ from those of conventional therapies. Hence, CSCs that are inherently resistant to conventional therapies may be susceptible to oncolytic virus-mediated killing. Recent studies have shown that oncolytic viruses can efficiently kill CSCs in many types of cancer. Here, we discuss the mechanism through which CSCs can escape conventional therapies and how they may still be susceptible to different classes of oncolytic viruses. Furthermore, we provide a summary of recent studies that have tested oncolytic viruses on CSCs of different origins and discuss possible future directions for this fascinating subset of oncolytic virus research. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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