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1
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Kar S, Mehrotra S, Prajapati VK. From infection to remedy: Harnessing oncolytic viruses in cancer treatment. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:213-257. [PMID: 39978967 DOI: 10.1016/bs.apcsb.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.
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Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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2
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Liao KL, Watt KD. Adaptive Immunity Determines the Cancer Treatment Outcome of Oncolytic Virus and Anti-PD-1. Bull Math Biol 2025; 87:36. [PMID: 39878909 DOI: 10.1007/s11538-025-01413-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/09/2025] [Indexed: 01/31/2025]
Abstract
The immune checkpoint inhibitor, anti-programmed death protein-1 (anti-PD-1), enhances adaptive immunity to kill tumor cells, and the oncolytic virus (OV) triggers innate immunity to clear the infected tumor cells. We create a mathematical model to investigate how the interaction between adaptive and innate immunities under OV and anti-PD-1 affects tumor reduction. For different immunity strength, we create the corresponding virtual baseline patients and cohort patients to decipher the major factors determining the treatment outcome. Global sensitivity analysis indicates that adaptive immunity has more control on the treatment outcome than innate immunity, and whether anti-PD-1 cancels out the OV treatment efficacy depends on the OV dosage and the balance between clearance of infected tumor cells and OV by T cells. The optimal OV infection rate and dosage suggest that OV treatment is more sensitive to adaptive immunity than innate immunity. Our model prediction also indicates that tumor reduction is more sensitive to anti-PD-1 efficacy as adaptive immunity becomes stronger, and anti-PD-1 trends to cancel out the OV treatment efficacy as innate immunity becomes stronger. Based on these results, the recommended treatment protocol for patients with different immunity strength can be determined.
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Affiliation(s)
- Kang-Ling Liao
- Department of Mathematics, University of Manitoba, 340 UMSU University Centre, Winnipeg, MB, R3T 2N2, Canada.
| | - Kenton D Watt
- Department of Mathematics, University of Manitoba, 340 UMSU University Centre, Winnipeg, MB, R3T 2N2, Canada
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Kiaheyrati N, Babaei A, Ranji R, Bahadoran E, Taheri S, Farokhpour Z. Cancer therapy with the viral and bacterial pathogens: The past enemies can be considered the present allies. Life Sci 2024; 349:122734. [PMID: 38788973 DOI: 10.1016/j.lfs.2024.122734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024]
Abstract
Cancer continues to be one of the leading causes of mortality worldwide despite significant advancements in cancer treatment. Many difficulties have arisen as a result of the detrimental consequences of chemotherapy and radiotherapy as a common cancer therapy, such as drug inability to penetrate deep tumor tissue, and also the drug resistance in tumor cells continues to be a major concern. These obstacles have increased the need for the development of new techniques that are more selective and effective against cancer cells. Bacterial-based therapies and the use of oncolytic viruses can suppress cancer in comparison to other cancer medications. The tumor microenvironment is susceptible to bacterial accumulation and proliferation, which can trigger immune responses against the tumor. Oncolytic viruses (OVs) have also gained considerable attention in recent years because of their potential capability to selectively target and induce apoptosis in cancer cells. This review aims to provide a comprehensive summary of the latest literature on the role of bacteria and viruses in cancer treatment, discusses the limitations and challenges, outlines various strategies, summarizes recent preclinical and clinical trials, and emphasizes the importance of optimizing current strategies for better clinical outcomes.
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Affiliation(s)
- Niloofar Kiaheyrati
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Abouzar Babaei
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran.
| | - Reza Ranji
- Department of Genetics, Faculty of Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ensiyeh Bahadoran
- School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Shiva Taheri
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zahra Farokhpour
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
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4
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Duan S, Wang S, Qiao L, Yu X, Wang N, Chen L, Zhang X, Zhao X, Liu H, Wang T, Wu Y, Li N, Liu F. Oncolytic Virus-Driven Biotherapies from Bench to Bedside. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2206948. [PMID: 36879416 DOI: 10.1002/smll.202206948] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/17/2023] [Indexed: 06/08/2023]
Abstract
With advances in cancer biology and an ever-deepening understanding of molecular virology, oncolytic virus (OV)-driven therapies have developed rapidly and become a promising alternative to traditional cancer therapies. In recent years, satisfactory results for oncolytic virus therapy (OVT) are achieved at both the cellular and organismal levels, and efforts are being increasingly directed toward clinical trials. Unfortunately, OVT remains ineffective in these trials, especially when performed using only a single OV reagent. In contrast, integrated approaches, such as using immunotherapy, chemotherapy, or radiotherapy, alongside OVT have demonstrated considerable efficacy. The challenges of OVT in clinical efficacy include the restricted scope of intratumoral injections and poor targeting of intravenous administration. Further optimization of OVT delivery is needed before OVs become a viable therapy for tumor treatment. In this review, the development process and antitumor mechanisms of OVs are introduced. The advances in OVT delivery routes to provide perspectives and directions for the improvement of OVT delivery are highlighted. This review also discusses the advantages and limitations of OVT monotherapy and combination therapy through the lens of recent clinical trials and aims to chart a course toward safer and more effective OVT strategies.
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Affiliation(s)
- Shijie Duan
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Shuhang Wang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lei Qiao
- Colorectal and Henia Minimally Invasive Surgery Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xinbo Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Nan Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Liting Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xinyuan Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xu Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Hongyu Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Tianye Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ying Wu
- Phase I Clinical Trials Center, The First Hospital of China Medical University, Department of General Practice, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ning Li
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Funan Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
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Tang N, Chen P, Zhao C, Liu P, Tan L, Song C, Qiu X, Liao Y, Liu X, Luo T, Sun Y, Ding C. Newcastle Disease Virus Manipulates Mitochondrial MTHFD2-Mediated Nucleotide Metabolism for Virus Replication. J Virol 2023; 97:e0001623. [PMID: 36794935 PMCID: PMC10062132 DOI: 10.1128/jvi.00016-23] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 01/22/2023] [Indexed: 02/17/2023] Open
Abstract
Viruses require host cell metabolic reprogramming to satisfy their replication demands; however, the mechanism by which the Newcastle disease virus (NDV) remodels nucleotide metabolism to support self-replication remains unknown. In this study, we demonstrate that NDV relies on the oxidative pentose phosphate pathway (oxPPP) and the folate-mediated one-carbon metabolic pathway to support replication. In concert with [1,2-13C2] glucose metabolic flow, NDV used oxPPP to promote pentose phosphate synthesis and to increase antioxidant NADPH production. Metabolic flux experiments using [2,3,3-2H] serine revealed that NDV increased one-carbon (1C) unit synthesis flux through the mitochondrial 1C pathway. Interestingly, methylenetetrahydrofolate dehydrogenase (MTHFD2) was upregulated as a compensatory mechanism for insufficient serine availability. Unexpectedly, direct knockdown of enzymes in the one-carbon metabolic pathway, except for cytosolic MTHFD1, significantly inhibited NDV replication. Specific complementation rescue experiments on small interfering RNA (siRNA)-mediated knockdown further revealed that only a knockdown of MTHFD2 strongly restrained NDV replication and was rescued by formate and extracellular nucleotides. These findings indicated that NDV replication relies on MTHFD2 to maintain nucleotide availability. Notably, nuclear MTHFD2 expression was increased during NDV infection and could represent a pathway by which NDV steals nucleotides from the nucleus. Collectively, these data reveal that NDV replication is regulated by the c-Myc-mediated 1C metabolic pathway and that the mechanism of nucleotide synthesis for viral replication is regulated by MTHFD2. IMPORTANCE Newcastle disease virus (NDV) is a dominant vector for vaccine and gene therapy that accommodates foreign genes well but can only infect mammalian cells that have undergone cancerous transformation. Understanding the remodeling of nucleotide metabolic pathways in host cells by NDV proliferation provides a new perspective for the precise use of NDV as a vector or in antiviral research. In this study, we demonstrated that NDV replication is strictly dependent on pathways involved in redox homeostasis in the nucleotide synthesis pathway, including the oxPPP and the mitochondrial one-carbon pathway. Further investigation revealed the potential involvement of NDV replication-dependent nucleotide availability in promoting MTHFD2 nuclear localization. Our findings highlight the differential dependence of NDV on enzymes for one-carbon metabolism, and the unique mechanism of action of MTHFD2 in viral replication, thereby providing a novel target for antiviral or oncolytic virus therapy.
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Affiliation(s)
- Ning Tang
- Laboratory of Veterinary Microbiology and Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning, Guangxi, China
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P. R. China
| | - Pingyi Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, P. R. China
| | - Changrun Zhao
- Laboratory of Veterinary Microbiology and Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning, Guangxi, China
| | - Panrao Liu
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, P. R. China
| | - Lei Tan
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P. R. China
| | - Cuiping Song
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P. R. China
| | - Xusheng Qiu
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P. R. China
| | - Ying Liao
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P. R. China
| | - Xiufan Liu
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, P. R. China
| | - Tingrong Luo
- Laboratory of Veterinary Microbiology and Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning, Guangxi, China
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi, China
| | - Yingjie Sun
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P. R. China
| | - Chan Ding
- Laboratory of Veterinary Microbiology and Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning, Guangxi, China
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, P. R. China
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6
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Therapeutic Efficacy of Oncolytic Viruses in Fighting Cancer: Recent Advances and Perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3142306. [PMID: 35910836 PMCID: PMC9337963 DOI: 10.1155/2022/3142306] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/20/2022] [Accepted: 05/26/2022] [Indexed: 12/22/2022]
Abstract
Immunotherapy is at the cutting edge of modern cancer treatment. Innovative medicines have been developed with varying degrees of success that target all aspects of tumor biology: tumors, niches, and the immune system. Oncolytic viruses (OVs) are a novel and potentially immunotherapeutic approach for cancer treatment. OVs reproduce exclusively in cancer cells, causing the tumor mass to lyse. OVs can also activate the immune system in addition to their primary activity. Tumors create an immunosuppressive environment by suppressing the immune system’s ability to respond to tumor cells. By injecting OVs into the tumor, the immune system is stimulated, allowing it to generate a robust and long-lasting response against the tumor. The essential biological properties of oncolytic viruses, as well as the underlying mechanisms that enable their usage as prospective anticancer medicines, are outlined in this review. We also discuss the increased efficacy of virotherapy when combined with other cancer medications.
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Santos Apolonio J, Lima de Souza Gonçalves V, Cordeiro Santos ML, Silva Luz M, Silva Souza JV, Rocha Pinheiro SL, de Souza WR, Sande Loureiro M, de Melo FF. Oncolytic virus therapy in cancer: A current review. World J Virol 2021; 10:229-255. [PMID: 34631474 PMCID: PMC8474975 DOI: 10.5501/wjv.v10.i5.229] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate "danger signals" that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.
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Affiliation(s)
- Jonathan Santos Apolonio
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - João Victor Silva Souza
- Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Wedja Rafaela de Souza
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
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Senekal NS, Mahasa KJ, Eladdadi A, de Pillis L, Ouifki R. Natural Killer Cells Recruitment in Oncolytic Virotherapy: A Mathematical Model. Bull Math Biol 2021; 83:75. [PMID: 34008149 DOI: 10.1007/s11538-021-00903-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 04/20/2021] [Indexed: 01/17/2023]
Abstract
In this paper, we investigate how natural killer (NK) cell recruitment to the tumor microenvironment (TME) affects oncolytic virotherapy. NK cells play a major role against viral infections. They are, however, known to induce early viral clearance of oncolytic viruses, which hinders the overall efficacy of oncolytic virotherapy. Here, we formulate and analyze a simple mathematical model of the dynamics of the tumor, OV and NK cells using currently available preclinical information. The aim of this study is to characterize conditions under which the synergistic balance between OV-induced NK responses and required viral cytopathicity may or may not result in a successful treatment. In this study, we found that NK cell recruitment to the TME must take place neither too early nor too late in the course of OV infection so that treatment will be successful. NK cell responses are most influential at either early (partly because of rapid response of NK cells to viral infections or antigens) or later (partly because of antitumoral ability of NK cells) stages of oncolytic virotherapy. The model also predicts that: (a) an NK cell response augments oncolytic virotherapy only if viral cytopathicity is weak; (b) the recruitment of NK cells modulates tumor growth; and (c) the depletion of activated NK cells within the TME enhances the probability of tumor escape in oncolytic virotherapy. Taken together, our model results demonstrate that OV infection is crucial, not just to cytoreduce tumor burden, but also to induce the stronger NK cell response necessary to achieve complete or at least partial tumor remission. Furthermore, our modeling framework supports combination therapies involving NK cells and OV which are currently used in oncolytic immunovirotherapy to treat several cancer types.
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Affiliation(s)
- Noma Susan Senekal
- Department of Mathematics and Computer Science, National University of Lesotho, Roma, Maseru, Lesotho.
| | - Khaphetsi Joseph Mahasa
- Department of Mathematics and Computer Science, National University of Lesotho, Roma, Maseru, Lesotho
| | | | | | - Rachid Ouifki
- Department of Mathematics and Applied Mathematics, University of Pretoria, Pretoria, South Africa
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9
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Cao GD, He XB, Sun Q, Chen S, Wan K, Xu X, Feng X, Li PP, Chen B, Xiong MM. The Oncolytic Virus in Cancer Diagnosis and Treatment. Front Oncol 2020; 10:1786. [PMID: 33014876 PMCID: PMC7509414 DOI: 10.3389/fonc.2020.01786] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/11/2020] [Indexed: 12/28/2022] Open
Abstract
Cancer has always been an enormous threat to human health and survival. Surgery, radiotherapy, and chemotherapy could improve the survival of cancer patients, but most patients with advanced cancer usually have a poor survival or could not afford the high cost of chemotherapy. The emergence of oncolytic viruses provided a new strategy for us to alleviate or even cure malignant tumors. An oncolytic virus can be described as a genetically engineered or naturally existing virus that can selectively replicate in cancer cells and then kill them without damaging the healthy cells. There have been many kinds of oncolytic viruses, such as herpes simplex virus, adenovirus, and Coxsackievirus. Moreover, they have different clinical applications in cancer treatment. This review focused on the clinical application of oncolytic virus and predicted the prospect by analyzing the advantages and disadvantages of oncolytic virotherapy.
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Affiliation(s)
- Guo-dong Cao
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiao-bo He
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiang Sun
- Jiangsu Key Laboratory of Biological Cancer, Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Sihan Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ke Wan
- Department of Oncology, Anhui Medical University, Hefei, China
| | - Xin Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xudong Feng
- Department of Infectious Disease, Zhejiang University, Hangzhou, China
| | - Peng-ping Li
- Department of General Surgery, The First People’s Hospital of Xiaoshan District, Hangzhou, China
| | - Bo Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mao-ming Xiong
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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10
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PET biomarkers and probes for treatment response assessment in glioblastoma: a work in progress. Clin Transl Imaging 2019. [DOI: 10.1007/s40336-019-00329-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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11
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Pearl TM, Markert JM, Cassady KA, Ghonime MG. Oncolytic Virus-Based Cytokine Expression to Improve Immune Activity in Brain and Solid Tumors. MOLECULAR THERAPY-ONCOLYTICS 2019; 13:14-21. [PMID: 30997392 PMCID: PMC6453942 DOI: 10.1016/j.omto.2019.03.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Oncolytic viral therapy has gained significant traction as cancer therapy over the past 2 decades. Oncolytic viruses are uniquely designed both to lyse tumor cells through their replication and to recruit immune responses against virally infected cells. Increasingly, investigators are leveraging this immune response to target the immunosuppressive tumor microenvironment and improve immune effector response against bystander tumor cells. In this article, we review the spectrum of preclinical, early-stage clinical, and potential future efforts with cytokine-secreting oncolytic viruses, with a focus on the treatment of brain tumors and solid tumors.
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Affiliation(s)
- Taylor M. Pearl
- The Ohio State University College of Medicine, Columbus, OH 43205, USA
| | - James M. Markert
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kevin A. Cassady
- The Ohio State University College of Medicine, Columbus, OH 43205, USA
- The Research Institute at Nationwide Children’s Hospital Center for Childhood Cancer and Blood Diseases, Columbus, OH 43205, USA
- Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Corresponding author: Kevin A. Cassady, Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH 43205, USA.
| | - Mohammed G. Ghonime
- The Research Institute at Nationwide Children’s Hospital Center for Childhood Cancer and Blood Diseases, Columbus, OH 43205, USA
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Berg DR, Offord CP, Kemler I, Ennis MK, Chang L, Paulik G, Bajzer Z, Neuhauser C, Dingli D. In vitro and in silico multidimensional modeling of oncolytic tumor virotherapy dynamics. PLoS Comput Biol 2019; 15:e1006773. [PMID: 30835721 PMCID: PMC6400333 DOI: 10.1371/journal.pcbi.1006773] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 01/10/2019] [Indexed: 01/23/2023] Open
Abstract
Tumor therapy with replication competent viruses is an exciting approach to cancer eradication where viruses are engineered to specifically infect, replicate, spread and kill tumor cells. The outcome of tumor virotherapy is complex due to the variable interactions between the cancer cell and virus populations as well as the immune response. Oncolytic viruses are highly efficient in killing tumor cells in vitro, especially in a 2D monolayer of tumor cells, their efficiency is significantly lower in a 3D environment, both in vitro and in vivo. This indicates that the spatial dimension may have a major influence on the dynamics of virus spread. We study the dynamic behavior of a spatially explicit computational model of tumor and virus interactions using a combination of in vitro 2D and 3D experimental studies to inform the models. We determine the number of nearest neighbor tumor cells in 2D (median = 6) and 3D tumor spheroids (median = 16) and how this influences virus spread and the outcome of therapy. The parameter range leading to tumor eradication is small and even harder to achieve in 3D. The lower efficiency in 3D exists despite the presence of many more adjacent cells in the 3D environment that results in a shorter time to reach equilibrium. The mean field mathematical models generally used to describe tumor virotherapy appear to provide an overoptimistic view of the outcomes of therapy. Three dimensional space provides a significant barrier to efficient and complete virus spread within tumors and needs to be explicitly taken into account for virus optimization to achieve the desired outcome of therapy.
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Affiliation(s)
- David R. Berg
- Department of Information Technology, Mayo Clinic, Rochester, Minnesota
| | | | - Iris Kemler
- Molecular Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Lawrence Chang
- Molecular Medicine, Mayo Clinic, Rochester, Minnesota
- Boston Children’s Hospital and Boston Medical Center, Boston, Massachusetts
| | - George Paulik
- International Business Machines, Rochester, Minnesota
| | - Zeljko Bajzer
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | | | - David Dingli
- Molecular Medicine, Mayo Clinic, Rochester, Minnesota
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Gujar S, Pol JG, Kim Y, Lee PW, Kroemer G. Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies. Trends Immunol 2017; 39:209-221. [PMID: 29275092 DOI: 10.1016/j.it.2017.11.006] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 11/20/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023]
Abstract
Oncolytic viruses (OVs) represent a new class of cancer immunotherapeutics. Administration of OVs to cancer-bearing hosts induces two distinct immunities: antiviral and antitumor. While antitumor immunity is beneficial, antiviral immune responses are often considered detrimental for the efficacy of OV-based therapy. The existing dogma postulates that anti-OV immune responses restrict viral replication and spread, and thus reduce direct OV-mediated killing of cancer cells. Accordingly, a myriad of therapeutic strategies aimed at mitigating anti-OV immune responses is presently being tested. Here, we advocate that OV-induced antiviral immune responses hold intrinsic anticancer benefits and are essential for establishing clinically desired antitumor immunity. Thus, to achieve the optimal efficacy of OV-based cancer immunotherapies, strategic management of anti-OV immune responses is of critical importance.
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Affiliation(s)
- Shashi Gujar
- Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, NS, Canada; Department of Biology, Dalhousie University, NS, Canada; Centre for Innovative and Collaborative Health Sciences Research, Quality and System Performance, IWK Health Centre, Halifax, NS, Canada; These authors contributed equally to this work
| | - Jonathan G Pol
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; These authors contributed equally to this work
| | - Youra Kim
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Patrick W Lee
- Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, NS, Canada; Share senior co-authorship.
| | - Guido Kroemer
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden; Share senior co-authorship.
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14
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15
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Kuhn I, Bauzon M, Green N, Seymour L, Fisher K, Hermiston T. OvAd1, a Novel, Potent, and Selective Chimeric Oncolytic Virus Developed for Ovarian Cancer by 3D-Directed Evolution. Mol Ther Oncolytics 2017; 4:55-66. [PMID: 28345024 PMCID: PMC5363728 DOI: 10.1016/j.omto.2016.12.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/01/2016] [Indexed: 02/07/2023] Open
Abstract
Effective therapeutics for ovarian cancer continue to be urgently needed, particularly for chemotherapy-resistant cases. Here we present both a 3D-Matrigel culture-based expansion of our directed evolution method for generation of oncolytic virotherapies and two promising ovarian-cancer targeted oncolytic viruses, OvAd1 and OvAd2. OvAd1 was developed using Matrigel cell cultures, whereas OvAd2 was developed in parallel using traditional monolayer tissue culture methods. Both viruses are potent against a panel of platinum-resistant ovarian cancer cell lines and are attenuated on normal cells in vitro, resulting in therapeutic windows of ∼200-fold. We observed two benefits of the use of Matrigel-based cultures for directed evolution of these oncolytics: (1) use of Matrigel generated a bioselected pool that was more strongly attenuated on normal cells while retaining its potency against ovarian cancer cells, and (2) in an ovarian carcinomatosis model, the Matrigel-derived virus OvAd1 suppressed all tumor growth while the non-Matrigel-derived virus was 50% effective. Neither virus stimulated formation of peritoneal adhesions as seen for Ad5-based therapies. Consequently, these viruses are novel candidates for development as new effective treatments for aggressive ovarian cancer.
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Affiliation(s)
- Irene Kuhn
- Department of Biological Research, Bayer Pharmaceuticals, 455 Mission Bay Boulevard South, Suite 493, San Francisco, CA 94158, USA
| | - Maxine Bauzon
- Department of Biological Research, Bayer Pharmaceuticals, 455 Mission Bay Boulevard South, Suite 493, San Francisco, CA 94158, USA
| | - Nicola Green
- Department of Clinical Medicine, University of Oxford, Old Road Campus, OX3 7DQ, Oxford, UK
| | - Len Seymour
- Department of Oncology, University of Oxford, Old Road Campus, OX3 7DQ, Oxford, UK
| | - Kerry Fisher
- Department of Oncology, University of Oxford, Old Road Campus, OX3 7DQ, Oxford, UK
| | - Terry Hermiston
- Department of Biological Research, Bayer Pharmaceuticals, 455 Mission Bay Boulevard South, Suite 493, San Francisco, CA 94158, USA
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16
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Conway C, Graham JL, Chengot P, Daly C, Chalkley R, Ross L, Droop A, Rabbitts P, Stead LF. Elucidating drivers of oral epithelial dysplasia formation and malignant transformation to cancer using RNAseq. Oncotarget 2016; 6:40186-201. [PMID: 26515596 PMCID: PMC4741888 DOI: 10.18632/oncotarget.5529] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 10/09/2015] [Indexed: 02/07/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent cancer with poor prognosis. Most OSCC progresses via a non-malignant stage called dysplasia. Effective treatment of dysplasia prior to potential malignant transformation is an unmet clinical need. To identify markers of early disease, we performed RNA sequencing of 19 matched HPV negative patient trios: normal oral mucosa, dysplasia and associated OSCC. We performed differential gene expression, principal component and correlated gene network analysis using these data. We found differences in the immune cell signatures present at different disease stages and were able to distinguish early events in pathogenesis, such as upregulation of many HOX genes, from later events, such as down-regulation of adherens junctions. We herein highlight novel coding and non-coding candidates for involvement in oral dysplasia development and malignant transformation, and speculate on how our findings may guide further translational research into the treatment of oral dysplasia.
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Affiliation(s)
- Caroline Conway
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.,Stratified Medicine (Oncology), School of Biomedical Sciences, University of Ulster, Coleraine, Co. Londonderry, BT52 1SA, UK
| | - Jennifer L Graham
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Preetha Chengot
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Catherine Daly
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Rebecca Chalkley
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Lisa Ross
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Alastair Droop
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Pamela Rabbitts
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Lucy F Stead
- Precancer Genomics, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK
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17
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Capitalizing on Cancer Specific Replication: Oncolytic Viruses as a Versatile Platform for the Enhancement of Cancer Immunotherapy Strategies. Biomedicines 2016; 4:biomedicines4030021. [PMID: 28536388 PMCID: PMC5344262 DOI: 10.3390/biomedicines4030021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 08/16/2016] [Accepted: 08/16/2016] [Indexed: 02/07/2023] Open
Abstract
The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being obtained in the last 5 years. It is becoming increasingly apparent that these two approaches are not mutually exclusive and that much of the therapeutic benefit obtained from the use of oncolytic viruses (OVs) is in fact the result of their immunotherapeutic function. Indeed, OVs have been shown to recruit and activate an antitumor immune response and much of the current work in this field centers around increasing this activity through strategies such as engineering genes for immunomodulators into OV backbones. Because of their broad immunostimulatory functions, OVs can also be rationally combined with a variety of other immunotherapeutic approaches including cancer vaccination strategies, adoptive cell transfer and checkpoint blockade. Therefore, while they are important therapeutics in their own right, the true power of OVs may lie in their ability to enhance the effectiveness of a wide range of immunotherapies.
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18
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Li X, Wang P, Li H, Du X, Liu M, Huang Q, Wang Y, Wang S. The Efficacy of Oncolytic Adenovirus Is Mediated by T-cell Responses against Virus and Tumor in Syrian Hamster Model. Clin Cancer Res 2016; 23:239-249. [PMID: 27435398 DOI: 10.1158/1078-0432.ccr-16-0477] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 06/23/2016] [Accepted: 06/25/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE Oncolytic adenoviruses (Ad) represent an innovative approach to cancer therapy. Its efficacy depends on multiple actions, including direct tumor lysis and stimulation of antiviral and antitumor immune responses. In this study, we investigated the roles of T-cell responses in oncolytic adenoviral therapy. EXPERIMENTAL DESIGN An immunocompetent and viral replication-permissive Syrian hamster tumor model was used. The therapeutic mechanisms of oncolytic Ad were investigated by T-cell deletion, immunohistochemical staining, and CTL assay. RESULTS Deletion of T cells with an anti-CD3 antibody completely demolished the antitumor efficacy of oncolytic Ad. Intratumoral injection of Ad induced strong virus- and tumor-specific T-cell responses, as well as antiviral antibody response. Both antiviral and antitumor T-cell responses contributed to the efficacy of oncolytic Ad. Deletion of T cells increased viral replication and extended the persistence of infectious virus within tumors but almost abrogated the antitumor efficacy. Preexisting antiviral immunity promoted the clearance of injected oncolytic Ad from tumors but had no effect on antitumor efficacy. Strikingly, the repeated treatment with oncolytic Ad has strong therapeutic effect on relapsed tumors or tumors insensitive to the primary viral therapy. CONCLUSIONS These results demonstrate that T cell-mediated immune responses outweigh the direct oncolysis in mediating antitumor efficacy of oncolytic Ad. Our data have a high impact on redesigning the regimen of oncolytic Ad for cancer treatment. Clin Cancer Res; 23(1); 239-49. ©2016 AACR.
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Affiliation(s)
- Xiaozhu Li
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Pengju Wang
- National Centre for International Research in Cell and Gene Therapy, Sino-British Research Center for Molecular Oncology, Zhengzhou University, Zhengzhou, China
| | - Hang Li
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xuexiang Du
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Mingyue Liu
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Qibin Huang
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Yaohe Wang
- National Centre for International Research in Cell and Gene Therapy, Sino-British Research Center for Molecular Oncology, Zhengzhou University, Zhengzhou, China.,Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Shengdian Wang
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
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19
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Cheng PH, Rao XM, Wechman SL, Li XF, McMasters KM, Zhou HS. Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice. BMC Cancer 2015; 15:716. [PMID: 26475304 PMCID: PMC4609153 DOI: 10.1186/s12885-015-1731-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 10/08/2015] [Indexed: 12/20/2022] Open
Abstract
Background Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads. Methods Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies. Results Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment. Conclusion Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1731-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Pei-Hsin Cheng
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Xiao-Mei Rao
- James Graham Brown Cancer Center, University of Louisville Medical School, 505 South Hancock Street, CTR Building, Room 306, Louisville, KY, 40202, USA.
| | - Stephen L Wechman
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. .,Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Xiao-Feng Li
- Department of Diagnostic Radiology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Kelly M McMasters
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. .,Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Heshan Sam Zhou
- James Graham Brown Cancer Center, University of Louisville Medical School, 505 South Hancock Street, CTR Building, Room 306, Louisville, KY, 40202, USA. .,Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA. .,Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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20
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Tsang JJ, Atkins HL. The ex vivo purge of cancer cells using oncolytic viruses: recent advances and clinical implications. Oncolytic Virother 2015; 4:13-23. [PMID: 27512666 PMCID: PMC4918373 DOI: 10.2147/ov.s45525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Hematological malignancies are treated with intensive high-dose chemotherapy, with or without radiation. This is followed by hematopoietic stem cell (HSC) transplantation (HSCT) to rescue or reconstitute hematopoiesis damaged by the anticancer therapy. Autologous HSC grafts may contain cancer cells and purging could further improve treatment outcomes. Similarly, allogeneic HSCT may be improved by selectively purging alloreactive effector cells from the graft rather than wholesale immune cell depletion. Viral agents that selectively replicate in specific cell populations are being studied in experimental models of cancer and immunological diseases and have potential applications in the context of HSC graft engineering. This review describes preclinical studies involving oncolytic virus strains of adenovirus, herpes simplex virus type 1, myxoma virus, and reovirus as ex vivo purging agents for HSC grafts, as well as in vitro and in vivo experimental studies using oncolytic coxsackievirus, measles virus, parvovirus, vaccinia virus, and vesicular stomatitis virus to eradicate hematopoietic malignancies. Alternative ex vivo oncolytic virus strategies are also outlined that aim to reduce the risk of relapse following autologous HSCT and mitigate morbidity and mortality due to graft-versus-host disease in allogeneic HSCT.
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Affiliation(s)
- Jovian J Tsang
- Department of Biochemistry, University of Ottawa, ON, Canada; Cancer Therapeutics, Ottawa Hospital Research Institute, ON, Canada
| | - Harold L Atkins
- Cancer Therapeutics, Ottawa Hospital Research Institute, ON, Canada; Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, ON, Canada
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21
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Roulstone V, Khan K, Pandha HS, Rudman S, Coffey M, Gill GM, Melcher AA, Vile R, Harrington KJ, de Bono J, Spicer J. Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors. Clin Cancer Res 2014; 21:1305-12. [PMID: 25424857 DOI: 10.1158/1078-0432.ccr-14-1770] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. EXPERIMENTAL DESIGN In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25-1,000 mg/m(2) through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. RESULTS The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m(2) combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. CONCLUSIONS Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.
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Affiliation(s)
- Victoria Roulstone
- Chester Beatty Laboratories, The Institute of Cancer Research, London, United Kingdom
| | - Khurum Khan
- Chester Beatty Laboratories, The Institute of Cancer Research, London, United Kingdom
| | - Hardev S Pandha
- Postgraduate Medical School, University of Surrey, Guildford, Surrey, United Kingdom
| | - Sarah Rudman
- King's College London, Guy's Hospital, London, United Kingdom
| | - Matt Coffey
- Oncolytics Biotech, Inc., Calgary, Alberta, Canada
| | | | - Alan A Melcher
- Leeds Institute of Cancer and Pathology, Leeds, United Kingdom
| | | | - Kevin J Harrington
- Chester Beatty Laboratories, The Institute of Cancer Research, London, United Kingdom
| | - Johann de Bono
- Royal Marsden Hospital, Down's Road, Sutton, Surrey, United Kingdom
| | - James Spicer
- King's College London, Guy's Hospital, London, United Kingdom.
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22
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CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol Ther 2014; 22:1949-59. [PMID: 25156126 DOI: 10.1038/mt.2014.160] [Citation(s) in RCA: 241] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 08/20/2014] [Indexed: 12/14/2022] Open
Abstract
We hypothesized that the combination of oncolytic virotherapy with immune checkpoint modulators would reduce tumor burden by direct cell lysis and stimulate antitumor immunity. In this study, we have generated attenuated Measles virus (MV) vectors encoding antibodies against CTLA-4 and PD-L1 (MV-aCTLA-4 and MV-aPD-L1). We characterized the vectors in terms of growth kinetics, antibody expression, and cytotoxicity in vitro. Immunotherapeutic effects were assessed in a newly established, fully immunocompetent murine model of malignant melanoma, B16-CD20. Analyses of tumor-infiltrating lymphocytes and restimulation experiments indicated a favorable immune profile after MV-mediated checkpoint modulation. Therapeutic benefits in terms of delayed tumor progression and prolonged median overall survival were observed for animals treated with vectors encoding anti-CTLA-4 and anti-PD-L1, respectively. Combining systemic administration of antibodies with MV treatment also improved therapeutic outcome. In vivo oncolytic efficacy against human tumors was studied in melanoma xenografts. MV-aCTLA-4 and MV-aPD-L1 were equally efficient as parental MV in this model, with high rates of complete tumor remission (> 80%). Furthermore, we could demonstrate lysis of tumor cells and transgene expression in primary tissue from melanoma patients. The current results suggest rapid translation of combining immune checkpoint modulation with oncolytic viruses into clinical application.
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Zajakina A, Vasilevska J, Zhulenkovs D, Skrastina D, Spaks A, Plotniece A, Kozlovska T. High efficiency of alphaviral gene transfer in combination with 5-fluorouracil in a mouse mammary tumor model. BMC Cancer 2014; 14:460. [PMID: 24950740 PMCID: PMC4077127 DOI: 10.1186/1471-2407-14-460] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 06/17/2014] [Indexed: 11/17/2022] Open
Abstract
Background The combination of virotherapy and chemotherapy may enable efficient tumor regression that would be unachievable using either therapy alone. In this study, we investigated the efficiency of transgene delivery and the cytotoxic effects of alphaviral vector in combination with 5-fluorouracil (5-FU) in a mouse mammary tumor model (4 T1). Methods Replication-deficient Semliki Forest virus (SFV) vectors carrying genes encoding fluorescent proteins were used to infect 4 T1 cell cultures treated with different doses of 5-FU. The efficiency of infection was monitored via fluorescence microscopy and quantified by fluorometry. The cytotoxicity of the combined treatment with 5-FU and alphaviral vector was measured using an MTT-based cell viability assay. In vivo experiments were performed in a subcutaneous 4 T1 mouse mammary tumor model with different 5-FU doses and an SFV vector encoding firefly luciferase. Results Infection of 4 T1 cells with SFV prior to 5-FU treatment did not produce a synergistic anti-proliferative effect. An alternative treatment strategy, in which 5-FU was used prior to virus infection, strongly inhibited SFV expression. Nevertheless, in vivo experiments showed a significant enhancement in SFV-driven transgene (luciferase) expression upon intratumoral and intraperitoneal vector administration in 4 T1 tumor-bearing mice pretreated with 5-FU: here, we observed a positive correlation between 5-FU dose and the level of luciferase expression. Conclusions Although 5-FU inhibited SFV-mediated transgene expression in 4 T1 cells in vitro, application of the drug in a mouse model revealed a significant enhancement of intratumoral transgene synthesis compared with 5-FU untreated mice. These results may have implications for efficient transgene delivery and the development of potent cancer treatment strategies using alphaviral vectors and 5-FU.
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Affiliation(s)
- Anna Zajakina
- Department of Cell Biology, Biomedical Research and Study Centre, Ratsupites Str,, 1, Riga LV-1067, Latvia.
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Combined cytolytic effects of a vaccinia virus encoding a single chain trimer of MHC-I with a Tax-epitope and Tax-specific CTLs on HTLV-I-infected cells in a rat model. BIOMED RESEARCH INTERNATIONAL 2014; 2014:902478. [PMID: 24791004 PMCID: PMC3985193 DOI: 10.1155/2014/902478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 02/20/2014] [Indexed: 02/01/2023]
Abstract
Adult T cell leukemia (ATL) is a malignant lymphoproliferative disease caused by human T cell leukemia virus type I (HTLV-I). To develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (VV), LC16m8Δ (m8Δ), and an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) line, 4O1/C8, against an HTLV-I-infected rat T cell line, FPM1. Our results demonstrated that m8Δ was able to replicate in and lyse tumorigenic FPM1 cells but was incompetent to injure 4O1/C8 cells, suggesting the preferential cytolytic activity toward tumor cells. To further enhance the cytolysis of HTLV-I-infected cells, we modified m8Δ and obtained m8Δ/RT1AlSCTax180L, which can express a single chain trimer (SCT) of rat major histocompatibility complex class I with a Tax-epitope. Combined treatment with m8Δ/RT1AlSCTax180L and 4O1/C8 increased the cytolysis of FPM1V.EFGFP/8R cells, a CTL-resistant subclone of FPM1, compared with that using 4O1/C8 and m8Δ presenting an unrelated peptide, suggesting that the activation of 4O1/C8 by m8Δ/RT1AlSCTax180L further enhanced the killing of the tumorigenic HTLV-I-infected cells. Our results indicate that combined therapy of oncolytic VVs with SCTs and HTLV-I-specific CTLs may be effective for eradication of HTLV-I-infected cells, which evade from CTL lysis and potentially develop ATL.
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Oncolytic virotherapy for osteosarcoma using midkine promoter-regulated adenoviruses. Cancer Gene Ther 2014; 21:126-32. [DOI: 10.1038/cgt.2014.7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 02/05/2014] [Indexed: 01/08/2023]
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Grossardt C, Engeland CE, Bossow S, Halama N, Zaoui K, Leber MF, Springfeld C, Jaeger D, von Kalle C, Ungerechts G. Granulocyte-macrophage colony-stimulating factor-armed oncolytic measles virus is an effective therapeutic cancer vaccine. Hum Gene Ther 2014; 24:644-54. [PMID: 23642239 DOI: 10.1089/hum.2012.205] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Oncolytic measles viruses (MV) derived from the live attenuated vaccine strain have been engineered for increased antitumor activity, and are currently under investigation in clinical phase 1 trials. Approaches with other viral vectors have shown that insertion of immunomodulatory transgenes enhances the therapeutic potency. In this study, we engineered MV for expression of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). For the first time, therapeutic efficacy and adaptive immune response in the context of MV oncolysis could be evaluated in the previously established immunocompetent murine colon adenocarcinoma model MC38cea. MC38cea cells express the human carcinoembryonic antigen (CEA), allowing for infection with retargeted MV. Intratumoral application of MV-GMCSF significantly delayed tumor progression and prolonged median overall survival compared with control virus-treated mice. Importantly, more than one-third of mice treated with MV-GMCSF showed complete tumor remission and rejected successive tumor reengraftment, demonstrating robust long-term protection. An enhanced cell-mediated tumor-specific immune response could be detected by lactate dehydrogenase assay and interferon-γ enzyme-linked immunospot assay. Furthermore, MV-GMCSF treatment correlated with increased abundance of tumor-infiltrating CD3(+) lymphocytes analyzed by quantitative microscopy of tumor sections. These findings underline the potential of oncolytic, GM-CSF-expressing MV as an effective therapeutic cancer vaccine actively recruiting adaptive immune responses for enhanced therapeutic impact and tumor elimination. Thus, the treatment benefit of this combined immunovirotherapy approach has direct implications for future clinical trials.
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Affiliation(s)
- Christian Grossardt
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ) , D-69120 Heidelberg, Germany
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Bailey K, Kirk A, Naik S, Nace R, Steele MB, Suksanpaisan L, Li X, Federspiel MJ, Peng KW, Kirk D, Russell SJ. Mathematical model for radial expansion and conflation of intratumoral infectious centers predicts curative oncolytic virotherapy parameters. PLoS One 2013; 8:e73759. [PMID: 24040057 PMCID: PMC3770695 DOI: 10.1371/journal.pone.0073759] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 07/21/2013] [Indexed: 01/24/2023] Open
Abstract
Simple, inductive mathematical models of oncolytic virotherapy are needed to guide protocol design and improve treatment outcomes. Analysis of plasmacytomas regressing after a single intravenous dose of oncolytic vesicular stomatitis virus in myeloma animal models revealed that intratumoral virus spread was spatially constrained, occurring almost exclusively through radial expansion of randomly distributed infectious centers. From these experimental observations we developed a simple model to calculate the probability of survival for any cell within a treated tumor. The model predicted that small changes to the density of initially infected cells or to the average maximum radius of infected centers would have a major impact on treatment outcome, and this was confirmed experimentally. The new model provides a useful and flexible tool for virotherapy protocol optimization.
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Affiliation(s)
- Kent Bailey
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Amber Kirk
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Shruthi Naik
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Rebecca Nace
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Michael B. Steele
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Lukkana Suksanpaisan
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Xing Li
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Mark J. Federspiel
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Kah-Whye Peng
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - David Kirk
- Consulpack, Inc., Minneapolis, Minnesota, United States of America
| | - Stephen J. Russell
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- * E-mail:
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Hasegawa N, Abei M, Yokoyama KK, Fukuda K, Seo E, Kawashima R, Nakano Y, Yamada T, Nakade K, Hamada H, Obata Y, Hyodo I. Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters. Int J Cancer 2013; 133:1479-88. [PMID: 23444104 DOI: 10.1002/ijc.28132] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2012] [Accepted: 02/07/2013] [Indexed: 12/16/2022]
Abstract
Oncolytic viruses (OVs) are novel cancer therapeutics with great promise, but host antiviral immunity represents the hurdle for their efficacy. Immunosuppression by cyclophosphamide (CP) has thus been shown to enhance the oncolytic efficacy of many OVs, but its effects on OVs armed with therapeutic genes remain unknown. We have previously reported on the efficacy of AxE1CAUP, an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), an enzyme that markedly enhanced the toxicity of 5-fluorouracil (5-FU), in immunodeficient, Ad-nonpermissive nude mice. Here we explored the efficacy and safety of intratumoral (i.t.) AxE1CAUP/5-FU therapy and of its combination with CP for syngenic HaP-T1 pancreatic cancers in immunocompetent, Ad-permissive Syrian hamsters. AxE1CAUP infected, replicated, expressed UPRT, and increased the sensitivity to 5-FU in HaP-T1 cells in vitro. I.t. AxE1CAUP/5-FU treatment inhibited the growth of subcutaneous HaP-T1 allografts. The combination with high-dose CP inhibited serum Ad-neutralizing antibody formation, increased intratumoral AxE1CAUP replication and UPRT expression, and resulted in further enhanced therapeutic effects with 5-FU. Neither body weight nor histology of the liver and lung changed during these treatments. A clinically-approved, intermediate-dose CP also enhanced the efficacy of i.t. AxE1CAUP/5-FU treatment in these hamsters, which was not affected by preexisting immunity to the vector. These data demonstrate the excellent antitumor efficacy and safety of an OAd armed with a suicide gene in combination with CP for treating syngenic tumors in immunocompetent, Ad-permissive animals, indicating the efficacy of CP in overcoming the hurdle of antiviral immunity for effective OV-mediated gene therapy.
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Affiliation(s)
- Naoyuki Hasegawa
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Biswas M, Kumar SR, Allen A, Yong W, Nimmanapalli R, Samal SK, Elankumaran S. Cell-type-specific innate immune response to oncolytic Newcastle disease virus. Viral Immunol 2012; 25:268-76. [PMID: 22808996 PMCID: PMC3413068 DOI: 10.1089/vim.2012.0020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 04/06/2012] [Indexed: 01/04/2023] Open
Abstract
Virotherapy of cancer exploits the potential of naturally occurring and engineered oncolytic viruses to selectively replicate in and cause cytotoxicity to tumor cells without affecting healthy normal cells. The tumor selectivity of Newcastle disease virus (NDV), a member of the family Paramyxoviridae, depends on the differential type I interferon (IFN) response. Further understanding of the key mechanisms and immune effector molecules involved will aid in augmenting the oncolytic properties of NDV. Here we report on the infection kinetics and innate immune responses to a recombinant LaSota strain of NDV (rLaSota eGFP) in human tumor and normal cells. We observed varying replicative fit and cytotoxicity of rLaSota eGFP depending on the tumor cell type, with severely restricted replication in normal cells. The absence of retinoic acid-inducible gene I (RIG-I), a cytosolic RNA sensor, determined sensitivity to NDV. Productive NDV infection with a moderate IFN-α induction in human multiple myeloma cells suggested a role for IFN-independent mechanisms or lack of type I IFN reinforcement by RIG-I. Proinflammatory cytokines and chemokines were altered differentially in infected normal and tumor cells. Our results suggest that tumor selectivity is dependent on variations in the cellular antiviral response to infection with NDV and RIG-I expression.
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Affiliation(s)
- Moanaro Biswas
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
| | - Sandeep R.P. Kumar
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
| | - Adria Allen
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
| | - Wang Yong
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
| | | | - Siba K. Samal
- Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland
| | - Subbiah Elankumaran
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
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Abstract
Twenty years of oncolytic virus development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding-more than 20 viruses have been recognized as potential oncolytic viruses-new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme. So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against glioblastoma multiforme. In this review, we present an overview of viruses that have been developed or considered for glioblastoma multiforme treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of oncolytic virus application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results; next-generation oncolytic viruses that are either "armed" with therapeutic genes or embedded in a multimodality treatment regimen should enhance the clinical results.
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Wang LCS, Lynn RC, Cheng G, Alexander E, Kapoor V, Moon EK, Sun J, Fridlender ZG, Isaacs SN, Thorne SH, Albelda SM. Treating tumors with a vaccinia virus expressing IFNβ illustrates the complex relationships between oncolytic ability and immunogenicity. Mol Ther 2012; 20:736-48. [PMID: 22008913 PMCID: PMC3321606 DOI: 10.1038/mt.2011.228] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 09/20/2011] [Indexed: 12/12/2022] Open
Abstract
Since previous work using a nonreplicating adenovirus-expressing mouse interferon-β (Ad.mIFNβ) showed promising preclinical activity, we postulated that a vector-expressing IFNβ at high levels that could also replicate would be even more beneficial. Accordingly a replication competent, recombinant vaccinia viral vector-expressing mIFNβ (VV.mIFNβ) was tested. VV.mIFNβ-induced antitumor responses in two syngeneic mouse flank models of lung cancer. Although VV.mIFNβ had equivalent in vivo efficacy in both murine tumor models, the mechanisms of tumor killing were completely different. In LKRM2 tumors, viral replication was minimal and the tumor killing mechanism was due to activation of immune responses through induction of a local inflammatory response and production of antitumor CD8 T-cells. In contrast, in TC-1 tumors, the vector replicated well, induced an innate immune response, but antitumor activity was primarily due to a direct oncolytic effect. However, the VV.mIFNβ vector was able to augment the efficacy of an antitumor vaccine in the TC-1 tumor model in association with increased numbers of infiltrating CD8 T-cells. These data show the complex relationships between oncolytic viruses and the immune system which, if understood and harnessed correctly, could potentially be used to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Liang-Chuan S Wang
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Rachel C Lynn
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Guanjun Cheng
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Edward Alexander
- Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Veena Kapoor
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Edmund K Moon
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jing Sun
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Zvi G Fridlender
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Stuart N Isaacs
- Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Stephen H Thorne
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Steven M Albelda
- Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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