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Wang M, Wang X, Jin X, Zhou J, Zhang Y, Yang Y, Liu Y, Zhang J. Cell-based and cell-free immunotherapies for glioblastoma: current status and future directions. Front Immunol 2023; 14:1175118. [PMID: 37304305 PMCID: PMC10248152 DOI: 10.3389/fimmu.2023.1175118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/08/2023] [Indexed: 06/13/2023] Open
Abstract
Glioblastoma (GBM) is among the most fatal and recurring malignant solid tumors. It arises from the GBM stem cell population. Conventional neurosurgical resection, temozolomide (TMZ)-dependent chemotherapy and radiotherapy have rendered the prognosis of patients unsatisfactory. Radiotherapy and chemotherapy can frequently induce non-specific damage to healthy brain and other tissues, which can be extremely hazardous. There is therefore a pressing need for a more effective treatment strategy for GBM to complement or replace existing treatment options. Cell-based and cell-free immunotherapies are currently being investigated to develop new treatment modalities against cancer. These treatments have the potential to be both selective and successful in minimizing off-target collateral harm in the normal brain. In this review, several aspects of cell-based and cell-free immunotherapies related to GBM will be discussed.
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Affiliation(s)
- Mingming Wang
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Xiaojie Wang
- Basic Medical School, Shenyang Medical College, Shenyang, Liaoning, China
| | - Xiaoyan Jin
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Jingjing Zhou
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Yufu Zhang
- Department of Hepatobiliary Surgery, the Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Yiyuan Yang
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Yusi Liu
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
| | - Jing Zhang
- Department of Cell Biology and Genetics, Medical College of Yan’an University, Yan’an, Shaanxi, China
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2
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Siew ZY, Loh A, Segeran S, Leong PP, Voon K. Oncolytic Reoviruses: Can These Emerging Zoonotic Reoviruses Be Tamed and Utilized? DNA Cell Biol 2023. [PMID: 37015068 DOI: 10.1089/dna.2022.0561] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2023] Open
Abstract
Orthoreovirus is a nonenveloped double-stranded RNA virus under the Reoviridae family. This group of viruses, especially mammalian orthoreovirus (MRV), are reported with great therapeutic values due to their oncolytic effects. In this review, the life cycle and oncolytic effect of MRV and a few emerging reoviruses were summarized. This article also highlights the challenges and strategies of utilizing MRV and the emerging reoviruses, avian orthoreovirus (ARV) and pteropine orthoreovirus (PRV), as oncolytic viruses (OVs). Besides, the emergence of potential ARV and PRV as OVs were discussed in comparison to MRV. Finally, the risk of reovirus as zoonosis or reverse zoonosis (zooanthroponosis) were debated, and concerns were raised in this article, which warrant continue surveillance of reovirus (MRV, ARV, and PRV) in animals, humans, and the environment.
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Affiliation(s)
- Zhen Yun Siew
- School of Pharmacy, University of Nottingham Malaysia, Semenyih, Malaysia
| | - Alson Loh
- School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
| | - Sharrada Segeran
- School of Medicine, Australian National University, Canberra, Australia
| | - Pooi Pooi Leong
- Faculty of Medicine and Health Sciences, Universiti of Tunku Abdul Rahman, Kajang, Malaysia
| | - Kenny Voon
- School of Pharmacy, University of Nottingham Malaysia, Semenyih, Malaysia
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3
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Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy. Viruses 2021; 13:v13040654. [PMID: 33920168 PMCID: PMC8070345 DOI: 10.3390/v13040654] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 12/11/2022] Open
Abstract
Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.
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Carey RM, Rajasekaran K, Seckar T, Lin X, Wei Z, Tong CCL, Ranasinghe VJ, Newman JG, O'Malley BW, Weinstein GS, Feldman MD, Robertson ES. The virome of HPV-positive tonsil squamous cell carcinoma and neck metastasis. Oncotarget 2020; 11:282-293. [PMID: 32076488 PMCID: PMC6980631 DOI: 10.18632/oncotarget.27436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 12/29/2019] [Indexed: 12/21/2022] Open
Abstract
Oropharyngeal squamous cell carcinoma (OPSCC) represents the most common HPV-related malignancy in the United States with increasing incidence. There is heterogeneity between the behavior and response to treatment of HPV-positive oropharyngeal squamous cell carcinoma that may be linked to the tumor virome. In this prospective study, a pan-pathogen microarray (PathoChip) was used to determine the virome of early stage, p16-positive OPSCC and neck metastasis treated with transoral robotic surgery (TORS) and neck dissection. The virome findings of primary tumors and neck lymph nodes were correlated with clinical data to determine if specific organisms were associated with clinical outcomes. A total of 114 patients were enrolled in the study. Double-stranded DNA viruses, specifically Papillomaviridae, showed the highest hybridization signal (viral copies) across all viral families in the primary and positive lymph node samples. High hybridization signals were also detected for signatures of Baculoviridae, Reoviridae, Siphoviridae, Myoviridae, and Polydnaviridae in most of the cancer specimens, including the lymph nodes without cancer present. Across all HPV signatures, HPV16 and 18 had the highest average hybridization signal index and prevalence. To our knowledge, this is the first study that has identified the viral signatures of OPSCC tumors. This will serve as a foundation for future research investigating the role of the virome in OPSCC. Further investigation into the OPSCC microbiome and its variations may allow for improved appreciation of the impact of microbial dysbiosis on risk stratification, oncologic outcomes, and treatment response which has been shown in other cancer sites.
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Affiliation(s)
- Ryan M Carey
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.,Co-first authors
| | - Karthik Rajasekaran
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.,Co-first authors
| | - Tyler Seckar
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Xiang Lin
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Zhi Wei
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Charles C L Tong
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Viran J Ranasinghe
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Jason G Newman
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Bert W O'Malley
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Gregory S Weinstein
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Michael D Feldman
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Erle S Robertson
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
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African Swine Fever Virus NP868R Capping Enzyme Promotes Reovirus Rescue during Reverse Genetics by Promoting Reovirus Protein Expression, Virion Assembly, and RNA Incorporation into Infectious Virions. J Virol 2017; 91:JVI.02416-16. [PMID: 28298603 DOI: 10.1128/jvi.02416-16] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/07/2017] [Indexed: 12/25/2022] Open
Abstract
Reoviruses, like many eukaryotic viruses, contain an inverted 7-methylguanosine (m7G) cap linked to the 5' nucleotide of mRNA. The traditional functions of capping are to promote mRNA stability, protein translation, and concealment from cellular proteins that recognize foreign RNA. To address the role of mRNA capping during reovirus replication, we assessed the benefits of adding the African swine fever virus NP868R capping enzyme during reovirus rescue. C3P3, a fusion protein containing T7 RNA polymerase and NP868R, was found to increase protein expression 5- to 10-fold compared to T7 RNA polymerase alone while enhancing reovirus rescue from the current reverse genetics system by 100-fold. Surprisingly, RNA stability was not increased by C3P3, suggesting a direct effect on protein translation. A time course analysis revealed that C3P3 increased protein synthesis within the first 2 days of a reverse genetics transfection. This analysis also revealed that C3P3 enhanced processing of outer capsid μ1 protein to μ1C, a previously described hallmark of reovirus assembly. Finally, to determine the rate of infectious-RNA incorporation into new virions, we developed a new recombinant reovirus S1 gene that expressed the fluorescent protein UnaG. Following transfection of cells with UnaG and infection with wild-type virus, passage of UnaG through progeny was significantly enhanced by C3P3. These data suggest that capping provides nontraditional functions to reovirus, such as promoting assembly and infectious-RNA incorporation.IMPORTANCE Our findings expand our understanding of how viruses utilize capping, suggesting that capping provides nontraditional functions to reovirus, such as promoting assembly and infectious-RNA incorporation, in addition to enhancing protein translation. Beyond providing mechanistic insight into reovirus replication, our findings also show that reovirus reverse genetics rescue is enhanced 100-fold by the NP868R capping enzyme. Since reovirus shows promise as a cancer therapy, efficient reovirus reverse genetics rescue will accelerate production of recombinant reoviruses as candidates to enhance therapeutic potency. NP868R-assisted reovirus rescue will also expedite production of recombinant reovirus for mechanistic insights into reovirus protein function and structure.
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Gong J, Sachdev E, Mita AC, Mita MM. Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity. World J Methodol 2016; 6:25-42. [PMID: 27019795 PMCID: PMC4804250 DOI: 10.5662/wjm.v6.i1.25] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 01/26/2016] [Accepted: 02/17/2016] [Indexed: 02/06/2023] Open
Abstract
Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus (Reolysin®) across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.
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Mohamed A, Johnston RN, Shmulevitz M. Potential for Improving Potency and Specificity of Reovirus Oncolysis with Next-Generation Reovirus Variants. Viruses 2015; 7:6251-78. [PMID: 26633466 PMCID: PMC4690860 DOI: 10.3390/v7122936] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Revised: 11/10/2015] [Accepted: 11/18/2015] [Indexed: 12/16/2022] Open
Abstract
Viruses that specifically replicate in tumor over normal cells offer promising cancer therapies. Oncolytic viruses (OV) not only kill the tumor cells directly; they also promote anti-tumor immunotherapeutic responses. Other major advantages of OVs are that they dose-escalate in tumors and can be genetically engineered to enhance potency and specificity. Unmodified wild type reovirus is a propitious OV currently in phase I–III clinical trials. This review summarizes modifications to reovirus that may improve potency and/or specificity during oncolysis. Classical genetics approaches have revealed reovirus variants with improved adaptation towards tumors or with enhanced ability to establish specific steps of virus replication and cell killing among transformed cells. The recent emergence of a reverse genetics system for reovirus has provided novel strategies to fine-tune reovirus proteins or introduce exogenous genes that could promote oncolytic activity. Over the next decade, these findings are likely to generate better-optimized second-generation reovirus vectors and improve the efficacy of oncolytic reotherapy.
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Affiliation(s)
- Adil Mohamed
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| | - Randal N Johnston
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Maya Shmulevitz
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
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Cooper T, Biron VL, Fast D, Tam R, Carey T, Shmulevitz M, Seikaly H. Oncolytic activity of reovirus in HPV positive and negative head and neck squamous cell carcinoma. J Otolaryngol Head Neck Surg 2015; 44:8. [PMID: 25890191 PMCID: PMC4348167 DOI: 10.1186/s40463-015-0062-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 02/09/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The management of patients with advanced stages of head and neck cancer requires a multidisciplinary and multimodality treatment approach which includes a combination of surgery, radiation, and chemotherapy. These toxic treatment protocols have significantly improved survival outcomes in a distinct population of human papillomavirus (HPV) associated oropharyngeal cancer. HPV negative head and neck squamous cell carcinoma (HNSCC) remains a challenge to treat because there is only a modest improvement in survival with the present treatment regimens, requiring innovative and new treatment approaches. Oncolytic viruses used as low toxicity adjunct cancer therapies are novel, potentially effective treatments for HNSCC. One such oncolytic virus is Respiratory Orphan Enteric virus or reovirus. Susceptibility of HNSCC cells towards reovirus infection and reovirus-induced cell death has been previously demonstrated but has not been compared in HPV positive and negative HNSCC cell lines. OBJECTIVES To compare the infectivity and oncolytic activity of reovirus in HPV positive and negative HNSCC cell lines. METHODS Seven HNSCC cell lines were infected with serial dilutions of reovirus. Two cell lines (UM-SCC-47 and UM-SCC-104) were positive for type 16 HPV. Infectivity was measured using a cell-based ELISA assay 18 h after infection. Oncolytic activity was determined using an alamar blue viability assay 96 h after infection. Non-linear regression models were used to calculate the amounts of virus required to infect and to cause cell death in 50% of a given cell line (EC50). EC50 values were compared. RESULTS HPV negative cells were more susceptible to viral infection and oncolysis compared to HPV positive cell lines. EC50 for infectivity at 18 h ranged from multiplicity of infection (MOI) values (PFU/cell) of 18.6 (SCC-9) to 3133 (UM-SCC 104). EC50 for cell death at 96 h ranged from a MOI (PFU/cell) of 1.02×10(2) (UM-SCC-14A) to 3.19×10(8) (UM-SCC-47). There was a 3×10(6) fold difference between the least susceptible cell line (UM-SCC-47) and the most susceptible line (UM-SCC 14A) EC50 for cell death at 96 h. CONCLUSIONS HPV negative HNSCC cell lines appear to demonstrate greater reovirus infectivity and virus-mediated oncolysis compared to HPV positive HNSCC. Reovirus shows promise as a novel therapy in HNSCC, and may be of particular benefit in HPV negative patients.
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Affiliation(s)
- Timothy Cooper
- Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Alberta, 1E4 University of Alberta Hospital, 1E4 Walter Mackenzie Center, 8440 112 St., Edmonton, AB, T6G 2B7, Canada.
| | - Vincent L Biron
- Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Alberta, 1E4 University of Alberta Hospital, 1E4 Walter Mackenzie Center, 8440 112 St., Edmonton, AB, T6G 2B7, Canada.
| | - David Fast
- Faculty of Science 1-001 CCIS, University of Alberta, Edmonton, AB, T6G 2E9, Canada.
| | - Raymond Tam
- Faculty of Medicine and Dentistry, University of Alberta, 2J2 WC Mackenzie Health Sciences Centre, Edmonton, AB, T6G 2R7, Canada.
| | - Thomas Carey
- Department of Head and Neck Surgery, University of Michigan, 5311B Med Sci I, Ann Arbor, MI, 48109-5616, USA.
| | - Maya Shmulevitz
- Department of Medical Microbiology and Immunology, University of Alberta, 6-142 J Katz Group Centre for Pharmacy & Health Research, Edmonton, AB, T6G 2E1, Canada.
| | - Hadi Seikaly
- Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Alberta, 1E4 University of Alberta Hospital, 1E4 Walter Mackenzie Center, 8440 112 St., Edmonton, AB, T6G 2B7, Canada.
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Reduction of virion-associated σ1 fibers on oncolytic reovirus variants promotes adaptation toward tumorigenic cells. J Virol 2015; 89:4319-34. [PMID: 25653434 DOI: 10.1128/jvi.03651-14] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED Wild-type mammalian orthoreovirus serotype 3 Dearing (T3wt) is nonpathogenic in humans but preferentially infects and kills cancer cells in culture and demonstrates promising antitumor activity in vivo. Using forward genetics, we previously isolated two variants of reovirus, T3v1 and T3v2, with increased infectivity toward a panel of cancer cell lines and improved in vivo oncolysis in a murine melanoma model relative to that of T3wt. Our current study explored how mutations in T3v1 and T3v2 promote infectivity. Reovirions contain trimers of σ1, the reovirus cell attachment protein, at icosahedral capsid vertices. Quantitative Western blot analysis showed that purified T3v1 and T3v2 virions had ∼ 2- and 4-fold-lower levels of σ1 fiber than did T3wt virions. Importantly, using RNA interference to reduce σ1 levels during T3wt production, we were able to generate wild-type reovirus with reduced levels of σ1 per virion. As σ1 levels were reduced, virion infectivity increased by 2- to 5-fold per cell-bound particle, demonstrating a causal relationship between virion σ1 levels and the infectivity of incoming virions. During infection of tumorigenic L929 cells, T3wt, T3v1, and T3v2 uncoated the outer capsid proteins σ3 and μ1C at similar rates. However, having started with fewer σ1 molecules, a complete loss of σ1 was achieved sooner for T3v1 and T3v2. Distinct from intracellular uncoating, chymotrypsin digestion, as a mimic of natural enteric infection, resulted in more rapid σ3 and μ1C removal, unique disassembly intermediates, and a rapid loss of infectivity for T3v1 and T3v2 compared to T3wt. Optimal infectivity toward natural versus therapeutic niches may therefore require distinct reovirus structures and σ1 levels. IMPORTANCE Wild-type reovirus is currently in clinical trials as a potential cancer therapy. Our molecular studies on variants of reovirus with enhanced oncolytic activity in vitro and in vivo now show that distinct reovirus structures promote adaptation toward cancer cells and away from conditions that mimic natural routes of infection. Specifically, we found that reovirus particles with fewer molecules of the cell attachment protein σ1 became more infectious toward transformed cells. Reduced σ1 levels conferred a benefit to incoming particles only, resulting in an earlier depletion of σ1 and a higher probability of establishing productive infection. Conversely, reovirus variants with fewer σ1 molecules showed reduced stability and infectivity and distinct disassembly when exposed to conditions that mimic natural intestinal proteolysis. These findings support a model where the mode of infection dictates the precise optimum of reovirus structure and provide a molecular rationale for considering alternative reovirus structures during oncolytic therapy.
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Abstract
Current mainstays in cancer treatment such as chemotherapy, radiation therapy, hormonal manipulation, and even targeted therapies such as Trastuzumab (herceptin) for breast cancer or Iressa (gefitinib) for non-small cell lung cancer among others are limited by lack of efficacy, cellular resistance, and toxicity. Dose escalation and combination therapies designed to overcome resistance and increase efficacy are limited by a narrow therapeutic index. Oncolytic viruses are one such group of new biological therapeutics that appears to have a wide spectrum of anticancer activity with minimal human toxicity. Since the malignant phenotype of tumors is the culmination of multiple mutations that occur in genes eventually leading to aberrant signaling pathways, oncolytic viruses either natural or engineered specifically target tumor cells taking advantage of this abnormal cellular signaling for their replication. Reovirus is one such naturally occurring double-stranded RNA virus that exploits altered signaling pathways (including Ras) in a myriad of cancers. The ability of reovirus to infect and lyse tumors under in vitro, in vivo, and ex vivo conditions has been well documented previously by us and others. The major mechanism of reovirus oncolysis of cancer cells has been shown to occur through apoptosis with autophagy taking place during this process in certain cancers. In addition, the synergistic antitumor effects of reovirus in combination with radiation or chemotherapy have also been demonstrated for reovirus resistant and moderately sensitive tumors. Recent progress in our understanding of viral immunology in the tumor microenvironment has diverted interest in exploring immunologic mechanisms to overcome resistance exhibited by chemotherapeutic drugs in cancer. Thus, currently several investigations are focusing on immune potentiating of reovirus for maximal tumor targeting. This chapter therefore has concentrated on immunologic cell death induction with reovirus as a novel approach to cancer therapy used under in vitro and in vivo conditions, as well as in a clinical setting. Reovirus phase I clinical trials have shown indications of efficacy, and several phase II/III trials are ongoing at present. Reovirus's extensive preclinical efficacy, replication competency, and low toxicity profile in humans have placed it as an attractive anticancer therapeutic for ongoing clinical testing that are highlighted in this chapter.
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11
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Progress in oncolytic virotherapy for the treatment of thyroid malignant neoplasm. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:91. [PMID: 25366264 PMCID: PMC4242545 DOI: 10.1186/s13046-014-0091-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 10/22/2014] [Indexed: 01/05/2023]
Abstract
Thyroid malignant neoplasm develops from follicular or parafollicular thyroid cells. A higher proportion of anaplastic thyroid cancer has an adverse prognosis. New drugs are being used in clinical treatment. However, for advanced thyroid malignant neoplasm such as anaplastic thyroid carcinoma, the major impediment to successful control of the disease is the absence of effective therapies. Oncolytic virotherapy has significantly progressed as therapeutics in recent years. The advance is that oncolytic viruses can be designed with biological specificity to infect, replicate and lyse tumor cells. Significant advances in virotherapy have being achieved to improve the accessibility, safety and efficacy of the treatment. Therefore, it is necessary to summarize and bring together the main areas covered by these investigations for the virotherapy of thyroid malignant neoplasm. We provide an overview of the progress in virotherapy research and clinical trials, which employ virotherapy for thyroid malignant neoplasm as well as the future prospect for virotherapy of thyroid malignant neoplasms.
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12
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Gong J, Mita MM. Activated ras signaling pathways and reovirus oncolysis: an update on the mechanism of preferential reovirus replication in cancer cells. Front Oncol 2014; 4:167. [PMID: 25019061 PMCID: PMC4071564 DOI: 10.3389/fonc.2014.00167] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 06/11/2014] [Indexed: 12/31/2022] Open
Abstract
The development of wild-type, unmodified Type 3 Dearing strain reovirus as an anticancer agent has currently expanded to 32 clinical trials (both completed and ongoing) involving reovirus in the treatment of cancer. It has been more than 30 years since the potential of reovirus as an anticancer agent was first identified in studies that demonstrated the preferential replication of reovirus in transformed cell lines but not in normal cells. Later investigations have revealed the involvement of activated Ras signaling pathways (both upstream and downstream) and key steps of the reovirus infectious cycle in promoting preferential replication in cancer cells with reovirus-induced cancer cell death occurring through necrotic, apoptotic, and autophagic pathways. There is increasing evidence that reovirus-induced antitumor immunity involving both innate and adaptive responses also contributes to therapeutic efficacy though this discussion is beyond the scope of this article. Here, we review our current understanding of the mechanism of oncolysis contributing to the broad anticancer activity of reovirus. Further understanding of reovirus oncolysis is critical in enhancing the clinical development and efficacy of reovirus.
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Affiliation(s)
- Jun Gong
- Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, CA , USA
| | - Monica M Mita
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, CA , USA
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13
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Errington F, White CL, Twigger KR, Rose A, Scott K, Steele L, Ilett LJ, Prestwich R, Pandha HS, Coffey M, Selby P, Vile R, Harrington KJ, Melcher AA. Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. Gene Ther 2008; 15:1257-70. [PMID: 18401435 PMCID: PMC4821075 DOI: 10.1038/gt.2008.58] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2007] [Revised: 02/21/2008] [Accepted: 02/23/2008] [Indexed: 12/18/2022]
Abstract
Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.
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Affiliation(s)
- F Errington
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
| | - CL White
- Targeted Therapy Laboratory, Chester Beatty Laboratories, Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, London, UK
| | - KR Twigger
- Targeted Therapy Laboratory, Chester Beatty Laboratories, Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, London, UK
| | - A Rose
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
| | - K Scott
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
| | - L Steele
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
| | - LJ Ilett
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
| | - R Prestwich
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
| | - HS Pandha
- Postgraduate Medical School, University of Surrey, Guildford, UK
| | - M Coffey
- Oncolytics Biotech Inc., Calgary, Canada
| | - P Selby
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
| | - R Vile
- Mayo Clinic, Rochester, MN, USA
| | - KJ Harrington
- Targeted Therapy Laboratory, Chester Beatty Laboratories, Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, London, UK
- Head and Neck Unit, Royal Marsden Hospital, London, UK
| | - AA Melcher
- Cancer Research UK Clinical Centre, St James’s University Hospital, University of Leeds, Leeds, UK
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Clarke P, Tyler KL. Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis. Apoptosis 2007; 12:211-23. [PMID: 17136319 PMCID: PMC2365758 DOI: 10.1007/s10495-006-0528-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) shows promise as a chemotherapeutic agent. However, many human cancer cells are resistant to killing by TRAIL. We have previously demonstrated that reovirus infection increases the susceptibility of human lung (H157) and breast (ZR75-1) cancer cell lines to TRAIL-induced apoptosis. We now show that reovirus also increases the susceptibility of human ovarian cancer cell lines (OVCAR3, PA-1 and SKOV-3) to TRAIL-induced apoptosis. Reovirus-induced increases in susceptibility of OVCAR3 cells to TRAIL require virus uncoating and involve increased activation of caspases 3 and 8. Reovirus infection results in the down-regulation of cFLIP (cellular FLICE inhibitory protein) in OVCAR3 cells. Down-regulation of cFLIP following treatment of OVCAR3 cells with antisense cFLIP oligonucleotides or PI3 kinase inhibition also increases the susceptibility of OVCAR3 cells to TRAIL-induced apoptosis. Finally, over-expression of cFLIP blocks reovirus-induced sensitization of OVCAR3 cells to TRAIL-induced apoptosis. The combination of reovirus and TRAIL thus represents a promising new therapeutic approach for the treatment of ovarian cancer.
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Affiliation(s)
- Penny Clarke
- Department of Neurology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B182, Denver, Colorado 80262, USA.
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