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Abrahams RR, Majumder K. Small Genomes, Big Disruptions: Parvoviruses and the DNA Damage Response. Viruses 2025; 17:494. [PMID: 40284937 PMCID: PMC12031541 DOI: 10.3390/v17040494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 03/25/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025] Open
Abstract
Parvoviruses are small, single-stranded DNA viruses that have evolved sophisticated mechanisms to hijack host cell machinery for replication and persistence. One critical aspect of this interaction involves the manipulation of the host's DNA Damage Response (DDR) pathways. While the viral genome is comparatively simple, parvoviruses have developed strategies that cause significant DNA damage, activate DDR pathways, and disrupt the host cell cycle. This review will explore the impact of parvovirus infections on host genome stability, focusing on key viral species such as Adeno-Associated Virus (AAV), Minute Virus of Mice (MVM), and Human Bocavirus (HBoV), and their interactions with DDR proteins. Since parvoviruses are used as oncolytic agents and gene therapy vectors, a better understanding of cellular DDR pathways will aid in engineering potent anti-cancer agents and gene therapies for chronic diseases.
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Affiliation(s)
| | - Kinjal Majumder
- Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53707, USA;
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2
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Shokoohi M, Sedaghatshoar S, Arian H, Mokarami M, Habibi F, Bamarinejad F. Genetic advancements in breast cancer treatment: a review. Discov Oncol 2025; 16:127. [PMID: 39918655 PMCID: PMC11805739 DOI: 10.1007/s12672-025-01884-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/03/2025] [Indexed: 02/09/2025] Open
Abstract
Breast cancer (BC) remains a leading cause of cancer-related deaths among women globally, highlighting the urgent need for more effective and targeted therapies. Traditional treatments, including surgery, chemotherapy, and radiation, face limitations such as drug resistance, metastasis, and severe side effects. Recent advancements in gene therapy, particularly CRISPR/Cas9 technology and Oncolytic Virotherapy (OVT), are transforming the BC treatment landscape. CRISPR/Cas9 enables precise gene editing to correct mutations in oncogenes like HER2 and MYC, directly addressing tumor growth and immune evasion. Simultaneously, OVT leverages genetically engineered viruses to selectively destroy cancer cells and stimulate robust antitumor immune responses. Despite their potential, gene therapies face challenges, including off-target effects, delivery issues, and ethical concerns. Innovations in delivery systems, combination strategies, and integrating gene therapy with existing treatments offer promising solutions to overcome these barriers. Personalized medicine, guided by genomic profiling, further enhances treatment precision by identifying patient-specific mutations, such as BRCA1 and BRCA2, allowing for more tailored and effective interventions. As research progresses, the constructive interaction between gene therapy, immunotherapy, and traditional approaches is paving the way for groundbreaking advancements in BC care. Continued collaboration between researchers and clinicians is essential to translate these innovations into clinical practice, ultimately improving BC patients' survival rates and quality of life.
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Affiliation(s)
- Marzieh Shokoohi
- Department of Life Sciences Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, Iran.
- Amino Techno Gene Virtual Private Laboratory, Tehran, Iran.
| | - Sadaf Sedaghatshoar
- Kent School of Social Work and Family Science, University of Louisville, Louisville, KY, USA
| | - Homaira Arian
- Pharmaceutical Biotechnology Department, Pharmacy Faculty, Anadolu University, Eskishehir, Turkey.
| | - Milad Mokarami
- Student Research Committee, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Habibi
- Department of Speech Therapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Bamarinejad
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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3
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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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Zhao JL, Lin BL, Luo C, Yi YL, Huang P, Chen Y, Zhao S, Huang ZJ, Ma XY, Huang L. Challenges and strategies toward oncolytic virotherapy for leptomeningeal metastasis. J Transl Med 2024; 22:1000. [PMID: 39501324 PMCID: PMC11539571 DOI: 10.1186/s12967-024-05794-4] [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: 08/12/2024] [Accepted: 10/22/2024] [Indexed: 11/08/2024] Open
Abstract
Meningeal metastasis (LM) is commonly seen in the advanced stages of cancer patients, often leading to a rapid decline in survival time and quality of life. Currently, there is still a lack of standardized treatments. Oncolytic viruses (OVs) are a class of emerging cancer therapeutics with the advantages of selectively replicating in cancer cells, delivering various eukaryotic transgenes, inducing immunogenic cell death, and promoting anti-tumor immunity. Some studies applying OVs intrathoracically or intraperitoneally for the treatment of malignant pleural and peritoneal effusions have shown promising therapeutic effects. If OVs could be applied to treat LM, it would bring significant survival benefits to patients with LM. In this review, we analyzed past research on the use of viruses to treat meningeal metastasis, summarized the efficacy and safety demonstrated by the research results, and analyzed the feasibility of oncolytic virus therapy for meningeal metastasis. We also summarized the existing data to provide guidance for the development of OVs that can be injected into the cerebrospinal fluid (CSF).
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Affiliation(s)
- Jia-Li Zhao
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Bi-Lin Lin
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Chen Luo
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Yan-Ling Yi
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Peng Huang
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Yu Chen
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Sha Zhao
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Zhen-Jie Huang
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Xin-Yi Ma
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China
| | - Long Huang
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Nanchang, Jiangxi, China.
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5
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Gujar S, Pol JG, Kumar V, Lizarralde-Guerrero M, Konda P, Kroemer G, Bell JC. Tutorial: design, production and testing of oncolytic viruses for cancer immunotherapy. Nat Protoc 2024; 19:2540-2570. [PMID: 38769145 DOI: 10.1038/s41596-024-00985-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 02/12/2024] [Indexed: 05/22/2024]
Abstract
Oncolytic viruses (OVs) represent a novel class of cancer immunotherapy agents that preferentially infect and kill cancer cells and promote protective antitumor immunity. Furthermore, OVs can be used in combination with established or upcoming immunotherapeutic agents, especially immune checkpoint inhibitors, to efficiently target a wide range of malignancies. The development of OV-based therapy involves three major steps before clinical evaluation: design, production and preclinical testing. OVs can be designed as natural or engineered strains and subsequently selected for their ability to kill a broad spectrum of cancer cells rather than normal, healthy cells. OV selection is further influenced by multiple factors, such as the availability of a specific viral platform, cancer cell permissivity, the need for genetic engineering to render the virus non-pathogenic and/or more effective and logistical considerations around the use of OVs within the laboratory or clinical setting. Selected OVs are then produced and tested for their anticancer potential by using syngeneic, xenograft or humanized preclinical models wherein immunocompromised and immunocompetent setups are used to elucidate their direct oncolytic ability as well as indirect immunotherapeutic potential in vivo. Finally, OVs demonstrating the desired anticancer potential progress toward translation in patients with cancer. This tutorial provides guidelines for the design, production and preclinical testing of OVs, emphasizing considerations specific to OV technology that determine their clinical utility as cancer immunotherapy agents.
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Affiliation(s)
- Shashi Gujar
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
| | - Jonathan G Pol
- INSERM, U1138, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Université Paris Cité, Paris, France
- Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Vishnupriyan Kumar
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
| | - Manuela Lizarralde-Guerrero
- INSERM, U1138, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Université Paris Cité, Paris, France
- Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Ecole Normale Supérieure de Lyon, Lyon, France
| | - Prathyusha Konda
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Harvard University, Boston, MA, USA
| | - Guido Kroemer
- INSERM, U1138, Paris, France.
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
- Université Paris Cité, Paris, France.
- Sorbonne Université, Paris, France.
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France.
- Institut Universitaire de France, Paris, France.
- Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - John C Bell
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
- Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada.
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
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6
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Karadimas T, Huynh TH, Chose C, Zervoudakis G, Clampitt B, Lapp S, Joyce D, Letson GD, Metts J, Binitie O, Mullinax JE, Lazarides A. Oncolytic Viral Therapy in Osteosarcoma. Viruses 2024; 16:1139. [PMID: 39066301 PMCID: PMC11281467 DOI: 10.3390/v16071139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/13/2024] [Accepted: 07/14/2024] [Indexed: 07/28/2024] Open
Abstract
Primary bone malignancies, including osteosarcoma (OS), are rare but aggressive. Current OS treatment, involving surgical resection and chemotherapy, has improved survival for non-metastatic cases but remains ineffective for recurrent or metastatic OS. Oncolytic viral therapy (OVT) is a promising alternative, using naturally occurring or genetically modified viruses to selectively target and lyse cancer cells and induce a robust immune response against remaining OS cells. Various oncolytic viruses (OVs), such as adenovirus, herpes simplex virus, and measles virus, have demonstrated efficacy in preclinical OS models. Combining OVT with other therapeutics, such as chemotherapy or immunotherapy, may further improve outcomes. Despite these advances, challenges in reliability of preclinical models, safety, delivery, and immune response must be addressed to optimize OVT for clinical use. Future research should focus on refining delivery methods, exploring combination treatments, and clinical trials to ensure OVT's efficacy and safety for OS. Overall, OVT represents a novel approach with the potential to drastically improve survival outcomes for patients with OS.
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Affiliation(s)
- Thomas Karadimas
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Thien Huong Huynh
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Chloe Chose
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Guston Zervoudakis
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Bryan Clampitt
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - Sean Lapp
- Morsani College of Medicine, University of South Florida Health, Tampa, FL 33602, USA; (T.H.H.); (C.C.); (B.C.); (S.L.)
| | - David Joyce
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - George Douglas Letson
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Jonathan Metts
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Odion Binitie
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - John E. Mullinax
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
| | - Alexander Lazarides
- Sarcoma Department, Moffitt Cancer Center, Tampa, FL 33612, USA; (G.Z.); (D.J.); (G.D.L.); (J.M.); (O.B.); (J.E.M.); (A.L.)
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7
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Eichhorn JS, Petrik J. Thetumor microenvironment'sinpancreatic cancer:Effects onimmunotherapy successandnovel strategiestoovercomethehostile environment. Pathol Res Pract 2024; 259:155370. [PMID: 38815507 DOI: 10.1016/j.prp.2024.155370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 05/26/2024] [Indexed: 06/01/2024]
Abstract
Cancer is a significant global health issue that poses a considerable burden on both patients and healthcare systems. Many different types of cancers exist that often require unique treatment approaches and therapies. A hallmark of tumor progression is the creation of an immunosuppressive environment, which poses complex challenges for current treatments. Amongst the most explored characteristics is a hypoxic environment, high interstitial pressure, and immunosuppressive cells and cytokines. Traditional cancer treatments involve radiotherapy, chemotherapy, and surgical procedures. The advent of immunotherapies was regarded as a promising approach with hopes of greatly increasing patients' survival and outcome. Although some success is seen with various immunotherapies, the vast majority of monotherapies are unsuccessful. This review examines how various aspects of the tumor microenvironment (TME) present challenges that impede the success of immunotherapies. Subsequently, we review strategies to manipulate the TME to facilitate the success of immunotherapies.
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Affiliation(s)
- Jan Sören Eichhorn
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1 Canada
| | - Jim Petrik
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1 Canada.
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Khanduja S, Bloom SM, Raman V, Deshpande CP, Hall CL, Forbes NS. Intracellular delivery of oncolytic viruses with engineered Salmonella causes viral replication and cell death. iScience 2024; 27:109813. [PMID: 38799578 PMCID: PMC11126981 DOI: 10.1016/j.isci.2024.109813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/12/2024] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
As therapies, oncolytic viruses regress tumors and have the potential to induce antitumor immune responses that clear hard-to-treat and late-stage cancers. Despite this promise, clearance from the blood prevents treatment of internal solid tumors. To address this issue, we developed virus-delivering Salmonella (VDS) to carry oncolytic viruses into cancer cells. The VDS strain contains the PsseJ-lysE delivery circuit and has deletions in four homologous recombination genes (ΔrecB, ΔsbcB, ΔsbcCD, and ΔrecF) to preserve essential hairpins in the viral genome required for replication and infectivity. VDS delivered the genome for minute virus of mice (MVMp) to multiple cancers, including breast, pancreatic, and osteosarcoma. Viral delivery produced functional viral particles that are cytotoxic and infective to neighboring cells. The release of mature virions initiated new rounds of infection and amplified the infection. Using Salmonella for delivery will circumvent the limitations of oncolytic viruses and will provide a new therapy for many cancers.
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Affiliation(s)
- Shradha Khanduja
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | - Shoshana M.K. Bloom
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | - Vishnu Raman
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | - Chinmay P. Deshpande
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | - Christopher L. Hall
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | - Neil S. Forbes
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
- Molecular and Cell Biology Program, University of Massachusetts, Amherst, Amherst, MA, USA
- Institute for Applied Life Science, University of Massachusetts, Amherst, Amherst, MA, USA
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9
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Iyer M, Ravichandran N, Karuppusamy PA, Gnanarajan R, Yadav MK, Narayanasamy A, Vellingiri B. Molecular insights and promise of oncolytic virus based immunotherapy. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 140:419-492. [PMID: 38762277 DOI: 10.1016/bs.apcsb.2023.12.007] [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: 05/20/2024]
Abstract
Discovering a therapeutic that can counteract the aggressiveness of this disease's mechanism is crucial for improving survival rates for cancer patients and for better understanding the most different types of cancer. In recent years, using these viruses as an anticancer therapy has been thought to be successful. They mostly work by directly destroying cancer cells, activating the immune system to fight cancer, and expressing exogenous effector genes. For the treatment of tumors, oncolytic viruses (OVs), which can be modified to reproduce only in tumor tissues and lyse them while preserving the healthy non-neoplastic host cells and reinstating antitumor immunity which present a novel immunotherapeutic strategy. OVs can exist naturally or be created in a lab by altering existing viruses. These changes heralded the beginning of a new era of less harmful virus-based cancer therapy. We discuss three different types of oncolytic viruses that have already received regulatory approval to treat cancer as well as clinical research using oncolytic adenoviruses. The primary therapeutic applications, mechanism of action of oncolytic virus updates, future views of this therapy will be covered in this chapter.
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Affiliation(s)
- Mahalaxmi Iyer
- Department of Microbiology, Central University of Punjab, Bathinda, India
| | - Nandita Ravichandran
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | | | - Roselin Gnanarajan
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Mukesh Kumar Yadav
- Department of Microbiology, Central University of Punjab, Bathinda, India
| | - Arul Narayanasamy
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, Tamil Nadu, India.
| | - Balachandar Vellingiri
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India.
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Chowaniec H, Ślubowska A, Mroczek M, Borowczyk M, Braszka M, Dworacki G, Dobosz P, Wichtowski M. New hopes for the breast cancer treatment: perspectives on the oncolytic virus therapy. Front Immunol 2024; 15:1375433. [PMID: 38576614 PMCID: PMC10991781 DOI: 10.3389/fimmu.2024.1375433] [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: 01/23/2024] [Accepted: 03/11/2024] [Indexed: 04/06/2024] Open
Abstract
Oncolytic virus (OV) therapy has emerged as a promising frontier in cancer treatment, especially for solid tumours. While immunotherapies like immune checkpoint inhibitors and CAR-T cells have demonstrated impressive results, their limitations in inducing complete tumour regression have spurred researchers to explore new approaches targeting tumours resistant to current immunotherapies. OVs, both natural and genetically engineered, selectively replicate within cancer cells, inducing their lysis while sparing normal tissues. Recent advancements in clinical research and genetic engineering have enabled the development of targeted viruses that modify the tumour microenvironment, triggering anti-tumour immune responses and exhibiting synergistic effects with other cancer therapies. Several OVs have been studied for breast cancer treatment, including adenovirus, protoparvovirus, vaccinia virus, reovirus, and herpes simplex virus type I (HSV-1). These viruses have been modified or engineered to enhance their tumour-selective replication, reduce toxicity, and improve oncolytic properties.Newer generations of OVs, such as Oncoviron and Delta-24-RGD adenovirus, exhibit heightened replication selectivity and enhanced anticancer effects, particularly in breast cancer models. Clinical trials have explored the efficacy and safety of various OVs in treating different cancers, including melanoma, nasopharyngeal carcinoma, head and neck cancer, and gynecologic malignancies. Notably, Talimogene laherparepvec (T-VEC) and Oncorine have. been approved for advanced melanoma and nasopharyngeal carcinoma, respectively. However, adverse effects have been reported in some cases, including flu-like symptoms and rare instances of severe complications such as fistula formation. Although no OV has been approved specifically for breast cancer treatment, ongoing preclinical clinical trials focus on four groups of viruses. While mild adverse effects like low-grade fever and nausea have been observed, the effectiveness of OV monotherapy in breast cancer remains insufficient. Combination strategies integrating OVs with chemotherapy, radiotherapy, or immunotherapy, show promise in improving therapeutic outcomes. Oncolytic virus therapy holds substantial potential in breast cancer treatment, demonstrating safety in trials. Multi-approach strategies combining OVs with conventional therapies exhibit more promising therapeutic effects than monotherapy, signalling a hopeful future for OV-based breast cancer treatments.
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Affiliation(s)
- Hanna Chowaniec
- Department of Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - Antonina Ślubowska
- Department of Biostatistics and Research Methodology, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University of Warsaw, Warsaw, Poland
| | - Magdalena Mroczek
- Department of Neurology, University Hospital Basel, Univeristy of Basel, Basel, Switzerland
| | - Martyna Borowczyk
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Małgorzata Braszka
- Faculty of Medical Sciences, University College London Medical School, London, United Kingdom
| | - Grzegorz Dworacki
- Department of Immunology, Poznan University of Medical Sciences, Poznan, Poland
- Chair of Patomorphology and Clinical Immunology, Poznań University of Medical Sciences, Poznan, Poland
| | - Paula Dobosz
- University Centre of Cancer Diagnostics, Poznan University of Medical Sciences, Poznan, Poland
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Mateusz Wichtowski
- Surgical Oncology Clinic, Institute of Oncology, Poznan University of Medical Sciences, Poznan, Poland
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11
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Angelova A, Rommelaere J, Ungerechts G. The Complex Role of Infectious Agents in Human Cutaneous T-Cell Lymphoma Pathogenesis: From Candidate Etiological Factors to Potential Therapeutics. Pathogens 2024; 13:184. [PMID: 38535528 PMCID: PMC10975429 DOI: 10.3390/pathogens13030184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/12/2024] [Accepted: 02/13/2024] [Indexed: 02/11/2025] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a devastating, potentially fatal T-lymphocyte malignancy affecting the skin. Despite all efforts, the etiology of this disease remains unknown. Infectious agents have long been suspected as factors or co-factors in CTCL pathogenesis. This review deals with the panel of bacterial and viral pathogens that have been investigated so far in an attempt to establish a potential link between infection/carriage and CTCL development. A special focus is given to a recently discovered human protoparvovirus, namely the cutavirus (CutaV), which has emerged as a plausible CTCL etiological agent. Available evidence in support of this hypothesis as well as alternative interpretations and uncertainties raised by some conflicting data are discussed. The complexity and multifacetedness of the Parvoviridae family of viruses are illustrated by presenting another protoparvovirus, the rat H-1 parvovirus (H-1PV). H-1PV belongs to the same genus as the CutaV but carries considerable potential for therapeutic applications in cutaneous lymphoma.
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Affiliation(s)
- Assia Angelova
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (J.R.); (G.U.)
| | - Jean Rommelaere
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (J.R.); (G.U.)
| | - Guy Ungerechts
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (J.R.); (G.U.)
- Department of Medical Oncology, National Center for Tumor Diseases Heidelberg and Heidelberg University Hospital, 69120 Heidelberg, Germany
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12
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Shah S. Novel Therapies in Glioblastoma Treatment: Review of Glioblastoma; Current Treatment Options; and Novel Oncolytic Viral Therapies. Med Sci (Basel) 2023; 12:1. [PMID: 38249077 PMCID: PMC10801585 DOI: 10.3390/medsci12010001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/15/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024] Open
Abstract
One of the most prevalent primary malignant brain tumors is glioblastoma (GB). About 6 incidents per 100,000 people are reported annually. Most frequently, these tumors are linked to a poor prognosis and poor quality of life. There has been little advancement in the treatment of GB. In recent years, some innovative medicines have been tested for the treatment of newly diagnosed cases of GB and recurrent cases of GB. Surgery, radiotherapy, and alkylating chemotherapy are all common treatments for GB. A few of the potential alternatives include immunotherapy, tumor-treating fields (TTFs), and medications that target specific cellular receptors. To provide new multimodal therapies that focus on the molecular pathways implicated in tumor initiation and progression in GB, novel medications, delivery technologies, and immunotherapy approaches are being researched. Of these, oncolytic viruses (OVs) are among the most recent. Coupling OVs with certain modern treatment approaches may have significant benefits for GB patients. Here, we discuss several OVs and how they work in conjunction with other therapies, as well as virotherapy for GB. The study was based on the PRISMA guidelines. Systematic retrieval of information was performed on PubMed. A total of 307 articles were found in a search on oncolytic viral therapies for glioblastoma. Out of these 83 articles were meta-analyses, randomized controlled trials, reviews, and systematic reviews. A total of 42 articles were from the years 2018 to 2023. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. One of the most prevalent malignant brain tumors is still GB. Significant promise and opportunity exist for oncolytic viruses in the treatment of GB and in boosting immune response. Making the most of OVs in the treatment of GB requires careful consideration and evaluation of a number of its application factors.
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Affiliation(s)
- Siddharth Shah
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA
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13
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Seyed-Khorrami SM, Azadi A, Rastegarvand N, Habibian A, Soleimanjahi H, Łos MJ. A promising future in cancer immunotherapy: Oncolytic viruses. Eur J Pharmacol 2023; 960:176063. [PMID: 37797673 DOI: 10.1016/j.ejphar.2023.176063] [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: 06/09/2023] [Revised: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 10/07/2023]
Abstract
Alongside the conventional methods, attention has been drawn to the use of immunotherapy-based methods for cancer treatment. Immunotherapy has developed as a therapeutic option that can be more specific with better outcomes in tumor treatment. It can boost or regulate the immune system behind the targeted virotherapy. Virotherapy is a kind of oncolytic immunotherapy that investigated broadly in cancer treatment in recent decades, due to its several advantages. According to recent advance in the field of understanding cancer cell biology and its occurrence, as well as increasing the knowledge about conditionally replicating oncolytic viruses and their destructive function in the tumor cells, nowadays, it is possible to apply this strategy in the treatment of malignancies. Relying on achievements in clinical trials of oncolytic viruses, we can certainly expect that this therapeutic perception can play a more central role in cancer treatment. In cancer treatment, combination therapy using oncolytic viruses alongside standard cancer treatment methods and other immunotherapy-based treatments can expect more promising results in the future.
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Affiliation(s)
| | - Arezou Azadi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nasrin Rastegarvand
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ala Habibian
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hoorieh Soleimanjahi
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, 8 Krzywousty St., 44-100, Gliwice, Poland; LinkoCare Life Sciences AB, Linkoping, Sweden.
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14
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Karandikar PV, Suh L, Gerstl JVE, Blitz SE, Qu QR, Won SY, Gessler FA, Arnaout O, Smith TR, Peruzzi PP, Yang W, Friedman GK, Bernstock JD. Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma. Front Cell Dev Biol 2023; 11:1271575. [PMID: 37860820 PMCID: PMC10582965 DOI: 10.3389/fcell.2023.1271575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the "immune-cold" nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response.
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Affiliation(s)
- Paramesh V. Karandikar
- T. H. Chan School of Medicine, University of Massachusetts, Worcester, MA, United States
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Lyle Suh
- T. H. Chan School of Medicine, University of Massachusetts, Worcester, MA, United States
| | - Jakob V. E. Gerstl
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Sarah E. Blitz
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Qing Rui Qu
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Sae-Yeon Won
- Department of Neurosurgery, University of Rostock, Rostock, Germany
| | | | - Omar Arnaout
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Timothy R. Smith
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Pier Paolo Peruzzi
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Wei Yang
- Department of Anesthesiology, Multidisciplinary Brain Protection Program, Duke University Medical Center, Durham, NC, United States
| | - Gregory K. Friedman
- Department of Neuro-Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, United States
| | - Joshua D. Bernstock
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
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15
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Kalafati E, Drakopoulou E, Anagnou NP, Pappa KI. Developing Oncolytic Viruses for the Treatment of Cervical Cancer. Cells 2023; 12:1838. [PMID: 37508503 PMCID: PMC10377776 DOI: 10.3390/cells12141838] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/09/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Cervical cancer represents one of the most important malignancies among women worldwide. Current therapeutic approaches for cervical cancer are reported not only to be inadequate for metastatic cervical cancer, but are also considered as cytotoxic for several patients leading to serious side effects, which can have negative implications on the quality of life of women. Therefore, there is an urgent need for the development of innovative and effective treatment options. Oncolytic viruses can eventually become effective biological agents, since they preferentially infect and kill cancer cells, while leaving the normal tissue unaffected. Moreover, they are also able to leverage the host immune system response to limit tumor growth. This review aims to systematically describe and discuss the different types of oncolytic viruses generated for targeting cervical cancer cells, as well as the outcome of the combination of virotherapy with conventional therapies. Although many preclinical studies have evaluated the therapeutic efficacy of oncolytic viruses in cervical cancer, the number of clinical trials so far is limited, while their oncolytic properties are currently being tested in clinical trials for the treatment of other malignancies.
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Affiliation(s)
- Eleni Kalafati
- Laboratory of Cell and Gene Therapy, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece
| | - Ekati Drakopoulou
- Laboratory of Cell and Gene Therapy, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece
| | - Nicholas P Anagnou
- Laboratory of Cell and Gene Therapy, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece
| | - Kalliopi I Pappa
- Laboratory of Cell and Gene Therapy, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece
- First Department of Obstetrics and Gynecology, University of Athens School of Medicine, 11528 Athens, Greece
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16
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Kingsak M, Meethong T, Jongkhumkrong J, Cai L, Wang Q. Therapeutic potential of oncolytic viruses in the era of precision oncology. BIOMATERIALS TRANSLATIONAL 2023; 4:67-84. [PMID: 38283919 PMCID: PMC10817786 DOI: 10.12336/biomatertransl.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 01/30/2024]
Abstract
Oncolytic virus (OV) therapy has been shown to be an effective targeted cancer therapy treatment in recent years, providing an avenue of treatment that poses no damage to surrounding healthy tissues. Not only do OVs cause direct oncolysis, but they also amplify both innate and adaptive immune responses generating long-term anti-tumour immunity. Genetically engineered OVs have become the common promising strategy to enhance anti-tumour immunity, safety, and efficacy as well as targeted delivery. The studies of various OVs have been accomplished through phase I-III clinical trial studies. In addition, the uses of carrier platforms of organic materials such as polymer chains, liposomes, hydrogels, and cell carriers have played a vital role in the potentially targeted delivery of OVs. The mechanism, rational design, recent clinical trials, applications, and the development of targeted delivery platforms of OVs will be discussed in this review.
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Affiliation(s)
- Monchupa Kingsak
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA
| | - Thongpon Meethong
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA
| | - Jinnawat Jongkhumkrong
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA
| | - Li Cai
- Department of Chemistry, University of South Carolina Lancaster, Lancaster, SC, USA
| | - Qian Wang
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA
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17
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Shahbaz A, Mahmood T, Javed MU, Abbasi BH. Current advances in microbial-based cancer therapies. Med Oncol 2023; 40:207. [PMID: 37330997 DOI: 10.1007/s12032-023-02074-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/05/2023] [Indexed: 06/20/2023]
Abstract
Microbes have an immense metabolic capability and can adapt to a wide variety of environments; as a result, they share complicated relationships with cancer. The goal of microbial-based cancer therapy is to treat patients with cancers that are not easily treatable, by using tumor-specific infectious microorganisms. Nevertheless, a number of difficulties have been encountered as a result of the harmful effects of chemotherapy, radiotherapy, and alternative cancer therapies, such as the toxicity to non-cancerous cells, the inability of medicines to penetrate deep tumor tissue, and the ongoing problem of rising drug resistance in tumor cells. Due to these difficulties, there is now a larger need for designing alternative strategies that are more effective and selective when targeting tumor cells. The fight against cancer has advanced significantly owing to cancer immunotherapy. The researchers have greatly benefited from their understanding of tumor-invading immune cells as well as the immune responses that are specifically targeted against cancer. Application of bacterial and viral cancer therapeutics offers promising potential to be employed as cancer treatments among immunotherapies. As a novel therapeutic strategy, microbial targeting of tumors has been created to address the persisting hurdles of cancer treatment. This review outlines the mechanisms by which both bacteria and viruses target and inhibit the proliferation of tumor cells. Their ongoing clinical trials and possible modifications that can be made in the future have also been addressed in the following sections. These microbial-based cancer medicines have the ability to suppress cancer that builds up and multiplies in the tumor microenvironment and triggers antitumor immune responses, in contrast to other cancer medications.
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Affiliation(s)
- Areej Shahbaz
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medicine Goettingen, Göttingen, Germany
| | - Tehreem Mahmood
- Department of Biotechnology, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Muhammad Uzair Javed
- Department of Biotechnology, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Bilal Haider Abbasi
- Department of Biotechnology, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
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18
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Hashida Y, Nakajima K, Higuchi T, Nakai K, Daibata M. Involvement of cutavirus in a subset of patients with cutaneous T-cell lymphoma with an unfavorable outcome. J Clin Virol 2023; 165:105523. [PMID: 37336173 DOI: 10.1016/j.jcv.2023.105523] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/04/2023] [Accepted: 06/14/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND European studies suggest an association between cutavirus (CuV) and cutaneous T-cell lymphoma (CTCL); however, the worldwide prevalence of CuV in patients with CTCL and its prognostic impact remain unknown. METHODS We investigated the prevalence and viral loads of CuV DNA using biopsy specimens from the lesional skins of 141 Japanese patients with cutaneous malignancies, including 55 patients with various types of CTCL. RESULTS CuV DNA was detected significantly more frequently in biopsies from patients with mycosis fungoides (MF) (38% [13/34]; the most common subtype of CTCL) than in those from patients with other cutaneous malignancies (6% [6/107]; P<0.001). The viral-load range in patients with CuV DNA-positive MF was 23-3922 copies/103 cells and 8-65 copies/μg of DNA. A phylogenetic analysis using the partial sequences of the CuV viral capsid protein 1 (VP1)/VP2 genes revealed that the CuV sequences identified here were clustered in a Japanese-specific clade distinct from that comprising CuV sequences from European patients with MF. Kaplan-Meier curves and a log-rank test showed that CuV positivity was associated with a shorter disease-specific survival in patients with MF (P = 0.031), whereas no significant difference in overall survival was observed (P = 0.275). No significant correlation was observed between CuV DNA load and survival in patients with CuV-positive MF. CONCLUSIONS Our results suggest that CuV is associated with MF in a subset of Japanese patients. Large-scale prospective studies are warranted to clarify the role of CuV status, especially regarding the viral genotype, on adverse outcomes in patients with CuV-positive MF.
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Affiliation(s)
- Yumiko Hashida
- Department of Microbiology and Infection, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
| | - Kimiko Nakajima
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
| | - Tomonori Higuchi
- Department of Microbiology and Infection, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
| | - Kozo Nakai
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
| | - Masanori Daibata
- Department of Microbiology and Infection, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
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19
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Angelova A, Pierrard K, Detje CN, Santiago E, Grewenig A, Nüesch JPF, Kalinke U, Ungerechts G, Rommelaere J, Daeffler L. Oncolytic Rodent Protoparvoviruses Evade a TLR- and RLR-Independent Antiviral Response in Transformed Cells. Pathogens 2023; 12:pathogens12040607. [PMID: 37111493 PMCID: PMC10144674 DOI: 10.3390/pathogens12040607] [Citation(s) in RCA: 4] [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: 02/27/2023] [Revised: 04/06/2023] [Accepted: 04/09/2023] [Indexed: 04/29/2023] Open
Abstract
The oncolytic rodent protoparvoviruses (PVs) minute virus of mice (MVMp) and H-1 parvovirus (H-1PV) are promising cancer viro-immunotherapy candidates capable of both exhibiting direct oncolytic activities and inducing anticancer immune responses (AIRs). Type-I interferon (IFN) production is instrumental for the activation of an efficient AIR. The present study aims at characterizing the molecular mechanisms underlying PV modulation of IFN induction in host cells. MVMp and H-1PV triggered IFN production in semi-permissive normal mouse embryonic fibroblasts (MEFs) and human peripheral blood mononuclear cells (PBMCs), but not in permissive transformed/tumor cells. IFN production triggered by MVMp in primary MEFs required PV replication and was independent of the pattern recognition receptors (PRRs) Toll-like (TLR) and RIG-like (RLR) receptors. PV infection of (semi-)permissive cells, whether transformed or not, led to nuclear translocation of the transcription factors NFĸB and IRF3, hallmarks of PRR signaling activation. Further evidence showed that PV replication in (semi-)permissive cells resulted in nuclear accumulation of dsRNAs capable of activating mitochondrial antiviral signaling (MAVS)-dependent cytosolic RLR signaling upon transfection into naïve cells. This PRR signaling was aborted in PV-infected neoplastic cells, in which no IFN production was detected. Furthermore, MEF immortalization was sufficient to strongly reduce PV-induced IFN production. Pre-infection of transformed/tumor but not of normal cells with MVMp or H-1PV prevented IFN production by classical RLR ligands. Altogether, our data indicate that natural rodent PVs regulate the antiviral innate immune machinery in infected host cells through a complex mechanism. In particular, while rodent PV replication in (semi-)permissive cells engages a TLR-/RLR-independent PRR pathway, in transformed/tumor cells this process is arrested prior to IFN production. This virus-triggered evasion mechanism involves a viral factor(s), which exert(s) an inhibitory action on IFN production, particularly in transformed/tumor cells. These findings pave the way for the development of second-generation PVs that are defective in this evasion mechanism and therefore endowed with increased immunostimulatory potential through their ability to induce IFN production in infected tumor cells.
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Affiliation(s)
- Assia Angelova
- Program Infection, Inflammation and Cancer, Clinical Cooperation Unit Virotherapy (F230), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Kristina Pierrard
- Program Infection, Inflammation and Cancer, Division Viral Transformation Mechanisms (F030), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Claudia N Detje
- Institute for Experimental Infection Research, TWICNORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | - Estelle Santiago
- CNRS, IPHC UMR 7178, Université de Strasbourg, F-67000 Strasbourg, France
| | - Annabel Grewenig
- Program Infection, Inflammation and Cancer, Division DNA Vectors (F160), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Jürg P F Nüesch
- Program Infection, Inflammation and Cancer, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWICNORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | - Guy Ungerechts
- Program Infection, Inflammation and Cancer, Clinical Cooperation Unit Virotherapy (F230), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Jean Rommelaere
- Program Infection, Inflammation and Cancer, Clinical Cooperation Unit Virotherapy (F230), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Laurent Daeffler
- CNRS, IPHC UMR 7178, Université de Strasbourg, F-67000 Strasbourg, France
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20
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Shi J, Pei Y, Yu Q, Dong H. Progress in the study of parvovirus entry pathway. Virol J 2023; 20:61. [PMID: 37016419 PMCID: PMC10072039 DOI: 10.1186/s12985-023-02016-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
A group of DNA viruses called parvoviruses that have significant effects on cancer therapy and genetic engineering applications. After passing through the cell membrane to reach the cytosol, it moves along the microtubule toward the nuclear membrane. The nuclear localization signal (NLS) is recognized by importin-beta (impβ) and other proteins from the complex outside the nuclear membrane and binds to enter the nucleus via the nuclear pore complex (NPC). There are two main pathways for viruses to enter the nucleus. The classical pathway is through the interaction of imp α and impβ with NLS via NPC. The other is the NPC mediated by the combination of impβ and it. While the capsid is introduced into the nucleus through classical nuclear transduction, there is also a transient nuclear membrane dissolution leading to passive transport into the nucleus, which has been proposed in recent years. This article mainly discusses several nuclear entry pathways and related proteins, providing a reference for subsequent research on viral entry pathways.
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Affiliation(s)
- Jiuming Shi
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin Province, China
| | - Yifeng Pei
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin Province, China
| | - Qian Yu
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin Province, China
| | - Hao Dong
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin Province, China.
- Engineering Research Center of Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun, 130118, China.
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21
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Hamad A, Yusubalieva GM, Baklaushev VP, Chumakov PM, Lipatova AV. Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies. Viruses 2023; 15:547. [PMID: 36851761 PMCID: PMC9958853 DOI: 10.3390/v15020547] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Glioblastoma is the most aggressive form of malignant brain tumor. Standard treatment protocols and traditional immunotherapy are poorly effective as they do not significantly increase the long-term survival of glioblastoma patients. Oncolytic viruses (OVs) may be an effective alternative approach. Combining OVs with some modern treatment options may also provide significant benefits for glioblastoma patients. Here we review virotherapy for glioblastomas and describe several OVs and their combination with other therapies. The personalized use of OVs and their combination with other treatment options would become a significant area of research aiming to develop the most effective treatment regimens for glioblastomas.
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Affiliation(s)
- Azzam Hamad
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Gaukhar M. Yusubalieva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia
| | - Vladimir P. Baklaushev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia
| | - Peter M. Chumakov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Anastasiya V. Lipatova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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22
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Hauswirth P, Graber P, Buczak K, Mancuso RV, Schenk SH, Nüesch JPF, Huwyler J. Design and Characterization of Mutated Variants of the Oncotoxic Parvoviral Protein NS1. Viruses 2023; 15:209. [PMID: 36680249 PMCID: PMC9866090 DOI: 10.3390/v15010209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/30/2022] [Accepted: 01/08/2023] [Indexed: 01/13/2023] Open
Abstract
Oncotoxic proteins such as the non-structural protein 1 (NS1), a constituent of the rodent parvovirus H1 (H1-PV), offer a novel approach for treatment of tumors that are refractory to other treatments. In the present study, mutated NS1 variants were designed and tested with respect to their oncotoxic potential in human hepatocellular carcinoma cell lines. We introduced single point mutations of previously described important residues of the wild-type NS1 protein and a deletion of 114 base pairs localized within the N-terminal domain of NS1. Cell-viability screening with HepG2 and Hep3B hepatocarcinoma cells transfected with the constructed NS1-mutants led to identification of the single-amino acid NS1-mutant NS1-T585E, which led to a 30% decrease in cell viability as compared to NS1 wildtype. Using proteomics analysis, we could identify new interaction partners and signaling pathways of NS1. We could thus identify new oncotoxic NS1 variants and gain insight into the modes of action of NS1, which is exclusively toxic to human cancer cells. Our in-vitro studies provide mechanistic explanations for the observed oncolytic effects. Expression of NS1 variants had no effect on cell viability in NS1 unresponsive control HepG2 cells or primary mouse hepatocytes. The availability of new NS1 variants in combination with a better understanding of their modes of action offers new possibilities for the design of innovative cancer treatment strategies.
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Affiliation(s)
- Patrick Hauswirth
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
| | - Philipp Graber
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
| | - Katarzyna Buczak
- Proteomics Core Facility, Biozentrum, University of Basel, 4056 Basel, Switzerland
| | - Riccardo Vincenzo Mancuso
- Division of Clinical Pharmacology & Toxicology, University Hospital of Basel, University of Basel, 4055 Basel, Switzerland
- Division of Molecular Pharmacy, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
| | - Susanne Heidi Schenk
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
| | - Jürg P. F. Nüesch
- Infection, Inflammation and Cancer Program, Division of Tumor Virology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Jörg Huwyler
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
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23
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Kaur T, Sharma D. Fundamentals of utilizing microbes in advanced cancer therapeutics: Current understanding and potential applications. ADVANCES IN APPLIED MICROBIOLOGY 2023. [PMID: 37400175 DOI: 10.1016/bs.aambs.2023.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
Abstract
One of the biggest health related issues in the twenty-first century is cancer. The current therapeutic platforms have not advanced enough to keep up with the number of rising cases. The traditional therapeutic approaches frequently fail to produce the desired outcomes. Therefore, developing new and more potent remedies is crucial. Recently, investigating microorganisms as potential anti-cancer treatments have garnered a lot of attention. Tumor-targeting microorganisms are more versatile at inhibiting cancer than the majority of standard therapies. Bacteria preferentially gather and thrive inside tumors, where they can trigger anti-cancer immune responses. They can be further trained to generate and distribute anticancer drugs based on clinical requirements using straightforward genetic engineering approaches. To improve clinical outcomes, therapeutic strategies utilizing live tumor-targeting bacteria can be used either alone or in combination with existing anticancer treatments. On the other hand, oncolytic viruses that target cancer cells, gene therapy via viral vectors, and viral immunotherapy are other popular areas of biotechnological investigation. Therefore, viruses serve as a unique candidate for anti-tumor therapy. This chapter describes the role of microbes, primarily bacteria and viruses in anti-cancer therapeutics. The various approaches to utilizing microbes in cancer therapy are discussed and examples of microorganisms that are now in use or that are undergoing experimental research are briefly discussed. We further point out the hurdles and the prospects of microbes-based remedies for cancer treatment.
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24
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Basu R, Moles CM. Rational selection of an ideal oncolytic virus to address current limitations in clinical translation. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023. [PMID: 37541726 DOI: 10.1016/bs.ircmb.2023.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Oncolytic virus therapy (OVT) is a promising modality that leverages the propensity of natural or engineered viruses to selectively replicate in and kill cancer cells. Over the past decade, (pre)clinical studies have focused on the development and testing of adenovirus, herpes simplex virus, and vaccinia virus-based vectors. These studies have identified barriers to success confronting the field. Here, we propose a set of selection criteria or ideal properties of a successful oncolytic virus, which include lack of pathogenicity, low seroprevalence, selectivity (infection and replication), transgene carrying capacity, and genome stability. We use these requirements to analyze the oncolytic virus landscape, and then identify a potentially optimal species for platform development - vesicular stomatitis virus.
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Abstract
Gene therapy is a powerful biological tool that is reshaping therapeutic landscapes for several diseases. Researchers are using both non-viral and viral-based gene therapy methods with success in the lab and the clinic. In the cancer biology field, gene therapies are expanding treatment options and the possibility of favorable outcomes for patients. While cellular immunotherapies and oncolytic virotherapies have paved the way in cancer treatments based on genetic engineering, recombinant adeno-associated virus (rAAV), a viral-based module, is also emerging as a potential cancer therapeutic through its malleability, specificity, and broad application to common as well as rare tumor types, tumor microenvironments, and metastatic disease. A wide range of AAV serotypes, promoters, and transgenes have been successful at reducing tumor growth and burden in preclinical studies, suggesting more groundbreaking advances using rAAVs in cancer are on the horizon.
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Affiliation(s)
- Patrick L. Mulcrone
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
- Department of Pediatrics, Indiana University, Indianapolis, IN 46202, USA
| | - Roland W. Herzog
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
| | - Weidong Xiao
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
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26
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Lauer UM, Beil J. Oncolytic viruses: challenges and considerations in an evolving clinical landscape. Future Oncol 2022; 18:2713-2732. [PMID: 35818970 DOI: 10.2217/fon-2022-0440] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Despite advances in treatment, cancer remains a leading cause of death worldwide. Although treatment strategies are continually progressing, cancers have evolved many mechanisms for evading therapies and the host immune system. Oncolytic viruses (OVs) could provide a much-needed option for cancers that are resistant to existing treatments. OVs can be engineered to specifically target and kill cancer cells, while simultaneously triggering an immune response at the site of infection. This review will focus on the challenges of developing a successful OV and translation to clinical practice, discussing the innovative strategies that are being used to optimize the potential of OVs. Here, we will also explore the current clinical landscape and the prospects of OVs in early clinical development.
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Affiliation(s)
- Ulrich M Lauer
- Department of Internal Medicine VIII, Virotherapy Center Tübingen, Medical Oncology & Pneumology, Medical University Hospital Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
| | - Julia Beil
- Department of Internal Medicine VIII, Virotherapy Center Tübingen, Medical Oncology & Pneumology, Medical University Hospital Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
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27
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Becker J, Fakhiri J, Grimm D. Fantastic AAV Gene Therapy Vectors and How to Find Them—Random Diversification, Rational Design and Machine Learning. Pathogens 2022; 11:pathogens11070756. [PMID: 35890005 PMCID: PMC9318892 DOI: 10.3390/pathogens11070756] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/30/2022] [Accepted: 07/01/2022] [Indexed: 11/16/2022] Open
Abstract
Parvoviruses are a diverse family of small, non-enveloped DNA viruses that infect a wide variety of species, tissues and cell types. For over half a century, their intriguing biology and pathophysiology has fueled intensive research aimed at dissecting the underlying viral and cellular mechanisms. Concurrently, their broad host specificity (tropism) has motivated efforts to develop parvoviruses as gene delivery vectors for human cancer or gene therapy applications. While the sum of preclinical and clinical data consistently demonstrates the great potential of these vectors, these findings also illustrate the importance of enhancing and restricting in vivo transgene expression in desired cell types. To this end, major progress has been made especially with vectors based on Adeno-associated virus (AAV), whose capsid is highly amenable to bioengineering, repurposing and expansion of its natural tropism. Here, we provide an overview of the state-of-the-art approaches to create new AAV variants with higher specificity and efficiency of gene transfer in on-target cells. We first review traditional and novel directed evolution approaches, including high-throughput screening of AAV capsid libraries. Next, we discuss programmable receptor-mediated targeting with a focus on two recent technologies that utilize high-affinity binders. Finally, we highlight one of the latest stratagems for rational AAV vector characterization and optimization, namely, machine learning, which promises to facilitate and accelerate the identification of next-generation, safe and precise gene delivery vehicles.
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Affiliation(s)
- Jonas Becker
- Department of Infectious Diseases/Virology, Medical Faculty, University of Heidelberg, Center for Integrative Infectious Diseases Research (CIID), BioQuant, 69120 Heidelberg, Germany;
- Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany
| | - Julia Fakhiri
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany
- Correspondence: (J.F.); (D.G.); Tel.: +49-174-3486203 (J.F.); +49-6221-5451331 (D.G.)
| | - Dirk Grimm
- Department of Infectious Diseases/Virology, Medical Faculty, University of Heidelberg, Center for Integrative Infectious Diseases Research (CIID), BioQuant, 69120 Heidelberg, Germany;
- German Center for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg, 69120 Heidelberg, Germany
- Correspondence: (J.F.); (D.G.); Tel.: +49-174-3486203 (J.F.); +49-6221-5451331 (D.G.)
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28
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Gupta M. Parvovirus Vectors: The Future of Gene Therapy. Vet Med Sci 2022. [DOI: 10.5772/intechopen.105085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The unique diversity of parvoviral vectors with innate antioncogenic properties, autonomous replication, ease of recombinant vector production and stable transgene expression in target cells makes them an attractive choice as viral vectors for gene therapy protocols. Amongst various parvoviruses that have been identified so far, recombinant vectors originating from adeno-associated virus, minute virus of mice (MVM), LuIII and parvovirus H1 have shown promising results in many preclinical models of human diseases including cancer. The adeno-associated virus (AAV), a non-pathogenic human parvovirus, has gained attention as a potentially useful vector. The improved understanding of the metabolism of vector genomes and the mechanism of transduction by AAV vectors is leading to advancement in the development of more sophisticated AAV vectors. The in-depth studies of AAV vector biology is opening avenues for more robust design of AAV vectors that have potentially increased transduction efficiency, increased specificity in cellular targeting, and an increased payload capacity. This chapter gives an overview of the application of autonomous parvoviral vectors and AAV vectors, based on our current understanding of viral biology and the state of the platform.
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29
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Shirbhate E, Veerasamy R, Boddu SH, Tiwari AK, Rajak H. Histone deacetylase inhibitor-based oncolytic virotherapy: a promising strategy for cancer treatment. Drug Discov Today 2022; 27:1689-1697. [DOI: 10.1016/j.drudis.2022.02.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 01/11/2022] [Accepted: 02/15/2022] [Indexed: 12/25/2022]
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30
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Andretta E, Costa C, Longobardi C, Damiano S, Giordano A, Pagnini F, Montagnaro S, Quintiliani M, Lauritano C, Ciarcia R. Potential Approaches Versus Approved or Developing Chronic Myeloid Leukemia Therapy. Front Oncol 2022; 11:801779. [PMID: 34993151 PMCID: PMC8724906 DOI: 10.3389/fonc.2021.801779] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/12/2021] [Indexed: 12/22/2022] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, continued use of these inhibitors has contributed to the increase in clinical resistance and the persistence of resistant leukemic stem cells (LSCs). So, there is an urgent need to introduce additional targeted and selective therapies to eradicate quiescent LSCs, and to avoid the relapse and disease progression. Here, we focused on emerging BCR-ABL targeted and non-BCR-ABL targeted drugs employed in clinical trials and on alternative CML treatments, including antioxidants, oncolytic virus, engineered exosomes, and natural products obtained from marine organisms that could pave the way for new therapeutic approaches for CML patients.
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Affiliation(s)
- Emanuela Andretta
- Department of Veterinary Medicine and Animal Productions, University of Naples "Federico II", Naples, Italy
| | - Caterina Costa
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Consiglia Longobardi
- Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Largo Madonna delle Grazie, Naples, Italy
| | - Sara Damiano
- Department of Veterinary Medicine and Animal Productions, University of Naples "Federico II", Naples, Italy
| | - Antonio Giordano
- Department of Medical Biotechnologies, University of Siena, Siena, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, United States
| | - Francesco Pagnini
- Unit of Radiology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Serena Montagnaro
- Department of Veterinary Medicine and Animal Productions, University of Naples "Federico II", Naples, Italy
| | | | - Chiara Lauritano
- Marine Biotechnology Department, Stazione Zoologica Anton Dohrn, Naples, Italy
| | - Roberto Ciarcia
- Department of Veterinary Medicine and Animal Productions, University of Naples "Federico II", Naples, Italy
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31
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Chen XT, Dai SY, Zhan Y, Yang R, Chen DQ, Li Y, Zhou EQ, Dong R. Progress of oncolytic virotherapy for neuroblastoma. Front Pediatr 2022; 10:1055729. [PMID: 36467495 PMCID: PMC9716318 DOI: 10.3389/fped.2022.1055729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/03/2022] [Indexed: 11/21/2022] Open
Abstract
As a neuroendocrine tumor derived from the neural crest, neuroblastoma (NB) is the most common extracranial solid tumor in children. The prognosis in patients with low- and intermediate-risk NB is favorable while that in high-risk patients is often detrimental. However, the management of the considerably large proportion of high-risk patients remains challenging in clinical practice. Among various new approaches, oncolytic virus (OV) therapy offers great advantages in tumor treatment, especially for high-risk NB. Genetic modified OVs can target NB specifically without affecting normal tissue and avoid the widespread drug resistance issue in anticancer monotherapy. Meanwhile, its safety profile provides great potential in combination therapy with chemo-, radio-, and immunotherapy. The therapeutic efficacy of OV for NB is impressive from bench to bedside. The effectiveness and safety of OVs have been demonstrated and reported in studies on children with NB. Furthermore, clinical trials on some OVs (Celyvir, Pexa-Vec (JX-594) and Seneca Valley Virus (NTX-010)) have reported great results. This review summarizes the latest evidence in the therapeutic application of OVs in NB, including those generated in cell lines, animal models and clinical trials.
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Affiliation(s)
- Xiao-Tong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Shu-Yang Dai
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Yong Zhan
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Ran Yang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - De-Qian Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Yi Li
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - En-Qing Zhou
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, China
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32
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Zeng J, Li X, Sander M, Zhang H, Yan G, Lin Y. Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas. Front Immunol 2021; 12:721830. [PMID: 34675919 PMCID: PMC8524046 DOI: 10.3389/fimmu.2021.721830] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/16/2021] [Indexed: 01/17/2023] Open
Abstract
The prognosis of malignant gliomas remains poor, with median survival fewer than 20 months and a 5-year survival rate merely 5%. Their primary location in the central nervous system (CNS) and its immunosuppressive environment with little T cell infiltration has rendered cancer therapies mostly ineffective, and breakthrough therapies such as immune checkpoint inhibitors (ICIs) have shown limited benefit. However, tumor immunotherapy is developing rapidly and can help overcome these obstacles. But for now, malignant gliomas remain fatal with short survival and limited therapeutic options. Oncolytic virotherapy (OVT) is a unique antitumor immunotherapy wherein viruses selectively or preferentially kill tumor cells, replicate and spread through tumors while inducing antitumor immune responses. OVTs can also recondition the tumor microenvironment and improve the efficacy of other immunotherapies by escalating the infiltration of immune cells into tumors. Some OVTs can penetrate the blood-brain barrier (BBB) and possess tropism for the CNS, enabling intravenous delivery. Despite the therapeutic potential displayed by oncolytic viruses (OVs), optimizing OVT has proved challenging in clinical development, and marketing approvals for OVTs have been rare. In June 2021 however, as a genetically engineered OV based on herpes simplex virus-1 (G47Δ), teserpaturev got conditional and time-limited approval for the treatment of malignant gliomas in Japan. In this review, we summarize the current state of OVT, the synergistic effect of OVT in combination with other immunotherapies as well as the hurdles to successful clinical use. We also provide some suggestions to overcome the challenges in treating of gliomas.
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Affiliation(s)
- Jiayi Zeng
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xiangxue Li
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Max Sander
- Department of International Cooperation, Guangzhou Virotech Pharmaceutical Co., Ltd., Guangzhou, China
| | - Haipeng Zhang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China
| | - Guangmei Yan
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuan Lin
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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33
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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: 72] [Impact Index Per Article: 18.0] [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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34
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Gil-Ranedo J, Gallego-García C, Almendral JM. Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations. Cell Rep 2021; 36:109673. [PMID: 34496248 DOI: 10.1016/j.celrep.2021.109673] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 04/05/2021] [Accepted: 08/16/2021] [Indexed: 10/20/2022] Open
Abstract
Cancer therapy urges targeting of malignant subsets within self-renewing heterogeneous stem cell populations. We dissect the genetic and functional heterogeneity of human glioblastoma stem cells (GSCs) within patients by their innate responses to non-pathogenic mouse parvoviruses that are tightly restrained by cellular physiology. GSC neurospheres accumulate assembled capsids but restrict viral NS1 cytotoxic protein expression by an innate PKR/eIF2α-P response counteractable by electric pulses. NS1 triggers a comprehensive DNA damage response involving cell-cycle arrest, neurosphere disorganization, and bystander disruption of GSC-derived brain tumor architecture in rodent models. GSCs and cancer cell lines permissive to parvovirus genome replication require p53-Ser15 phosphorylation (Pp53S15). NS1 expression is enhanced by exogeneous Pp53S15 induction but repressed by wtp53. Consistently, patient-specific GSC subpopulations harboring p53 gain-of-function mutants and/or Pp53S15 are selective viral targets. This study provides a molecular foundation for personalized biosafe viral therapies against devastating glioblastoma and other cancers with deregulated p53 signaling.
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Affiliation(s)
- Jon Gil-Ranedo
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid, Spain
| | - Carlos Gallego-García
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid, Spain
| | - José M Almendral
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid, Spain.
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35
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Mattola S, Hakanen S, Salminen S, Aho V, Mäntylä E, Ihalainen TO, Kann M, Vihinen-Ranta M. Concepts to Reveal Parvovirus-Nucleus Interactions. Viruses 2021; 13:1306. [PMID: 34372512 PMCID: PMC8310053 DOI: 10.3390/v13071306] [Citation(s) in RCA: 8] [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: 06/01/2021] [Revised: 06/24/2021] [Accepted: 07/02/2021] [Indexed: 01/23/2023] Open
Abstract
Parvoviruses are small single-stranded (ss) DNA viruses, which replicate in the nucleoplasm and affect both the structure and function of the nucleus. The nuclear stage of the parvovirus life cycle starts at the nuclear entry of incoming capsids and culminates in the successful passage of progeny capsids out of the nucleus. In this review, we will present past, current, and future microscopy and biochemical techniques and demonstrate their potential in revealing the dynamics and molecular interactions in the intranuclear processes of parvovirus infection. In particular, a number of advanced techniques will be presented for the detection of infection-induced changes, such as DNA modification and damage, as well as protein-chromatin interactions.
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Affiliation(s)
- Salla Mattola
- Department of Biological and Environmental Science, University of Jyvaskyla, 40500 Jyvaskyla, Finland; (S.M.); (S.H.); (S.S.); (V.A.)
| | - Satu Hakanen
- Department of Biological and Environmental Science, University of Jyvaskyla, 40500 Jyvaskyla, Finland; (S.M.); (S.H.); (S.S.); (V.A.)
| | - Sami Salminen
- Department of Biological and Environmental Science, University of Jyvaskyla, 40500 Jyvaskyla, Finland; (S.M.); (S.H.); (S.S.); (V.A.)
| | - Vesa Aho
- Department of Biological and Environmental Science, University of Jyvaskyla, 40500 Jyvaskyla, Finland; (S.M.); (S.H.); (S.S.); (V.A.)
| | - Elina Mäntylä
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (E.M.); (T.O.I.)
| | - Teemu O. Ihalainen
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (E.M.); (T.O.I.)
| | - Michael Kann
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden;
- Department of Clinical Microbiology, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden
| | - Maija Vihinen-Ranta
- Department of Biological and Environmental Science, University of Jyvaskyla, 40500 Jyvaskyla, Finland; (S.M.); (S.H.); (S.S.); (V.A.)
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Kulkarni A, Ferreira T, Bretscher C, Grewenig A, El-Andaloussi N, Bonifati S, Marttila T, Palissot V, Hossain JA, Azuaje F, Miletic H, Ystaas LAR, Golebiewska A, Niclou SP, Roeth R, Niesler B, Weiss A, Brino L, Marchini A. Oncolytic H-1 parvovirus binds to sialic acid on laminins for cell attachment and entry. Nat Commun 2021; 12:3834. [PMID: 34158478 PMCID: PMC8219832 DOI: 10.1038/s41467-021-24034-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 05/26/2021] [Indexed: 12/11/2022] Open
Abstract
H-1 parvovirus (H-1PV) is a promising anticancer therapy. However, in-depth understanding of its life cycle, including the host cell factors needed for infectivity and oncolysis, is lacking. This understanding may guide the rational design of combination strategies, aid development of more effective viruses, and help identify biomarkers of susceptibility to H-1PV treatment. To identify the host cell factors involved, we carry out siRNA library screening using a druggable genome library. We identify one crucial modulator of H-1PV infection: laminin γ1 (LAMC1). Using loss- and gain-of-function studies, competition experiments, and ELISA, we validate LAMC1 and laminin family members as being essential to H-1PV cell attachment and entry. H-1PV binding to laminins is dependent on their sialic acid moieties and is inhibited by heparin. We show that laminins are differentially expressed in various tumour entities, including glioblastoma. We confirm the expression pattern of laminin γ1 in glioblastoma biopsies by immunohistochemistry. We also provide evidence of a direct correlation between LAMC1 expression levels and H-1PV oncolytic activity in 59 cancer cell lines and in 3D organotypic spheroid cultures with different sensitivities to H-1PV infection. These results support the idea that tumours with elevated levels of γ1 containing laminins are more susceptible to H-1PV-based therapies.
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Affiliation(s)
- Amit Kulkarni
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
- Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Tiago Ferreira
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
| | - Clemens Bretscher
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
| | - Annabel Grewenig
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
| | - Nazim El-Andaloussi
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
- Lonza Cologne GmbH, Köln, Germany
| | - Serena Bonifati
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
- Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Tiina Marttila
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
- Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Valérie Palissot
- Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Jubayer A Hossain
- Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Department of Biomedicine, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Francisco Azuaje
- Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Genomics England, London, United Kingdom
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Lars A R Ystaas
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Anna Golebiewska
- NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Simone P Niclou
- NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Ralf Roeth
- nCounter Core Facility, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| | - Beate Niesler
- nCounter Core Facility, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| | - Amélie Weiss
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
| | - Laurent Brino
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
| | - Antonio Marchini
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany.
- Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health, Luxembourg, Luxembourg.
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Viral Proteins as Emerging Cancer Therapeutics. Cancers (Basel) 2021; 13:cancers13092199. [PMID: 34063663 PMCID: PMC8125098 DOI: 10.3390/cancers13092199] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/27/2021] [Accepted: 04/30/2021] [Indexed: 01/16/2023] Open
Abstract
Simple Summary This review is focused on enlisting viral proteins from different host sources, irrespective of their origin, that may act as future cancer curatives. Unlike the viral proteins that are responsible for tumor progression, these newly emerged viral proteins function as tumor suppressors. Their ability to regulate various cell signaling mechanisms specifically in cancer cells makes them interesting candidates to explore their use in cancer therapy. The discussion about such viral components may provide new insights into cancer treatment in the absence of any adverse effects to normal cells. The study also highlights avian viral proteins as a substitute to human oncolytic viruses for their ability to evade pre-existing immunity. Abstract Viruses are obligatory intracellular parasites that originated millions of years ago. Viral elements cover almost half of the human genome sequence and have evolved as genetic blueprints in humans. They have existed as endosymbionts as they are largely dependent on host cell metabolism. Viral proteins are known to regulate different mechanisms in the host cells by hijacking cellular metabolism to benefit viral replication. Amicable viral proteins, on the other hand, from several viruses can participate in mediating growth retardation of cancer cells based on genetic abnormalities while sparing normal cells. These proteins exert discreet yet converging pathways to regulate events like cell cycle and apoptosis in human cancer cells. This property of viral proteins could be harnessed for their use in cancer therapy. In this review, we discuss viral proteins from different sources as potential anticancer therapeutics.
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Yan YQ, Jin LB, Wang Y, Lu SY, Pei YF, Zhu DW, Pang FS, Dong H, Hu GX. Goose parvovirus and the protein NS1 induce apoptosis through the AIF-mitochondrial pathway in goose embryo fibroblasts. Res Vet Sci 2021; 137:68-76. [PMID: 33933710 DOI: 10.1016/j.rvsc.2021.04.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/06/2021] [Accepted: 04/13/2021] [Indexed: 10/21/2022]
Abstract
In this study, the effects of Goose parvovirus (GPV) infection as well as the possible role of NS1 protein on apoptosis induction in goose embryo fibroblast (GEF) cells were examined. Flow cytometry analysis and TUNEL assays revealed that GPV infection and NS1 transfection induced significant apoptosis in GEF cells compared to what was observed in mock-infected cells. Interestingly, the increase in the rate of apoptosis detected in GPV-infected GEFs was accompanied by an increased viral load in the cells. In addition, the apoptotic pathway was mediated by apoptosis-inducing factors (AIFs) and internal factors that influence the release of AIFs. The results indicated that the mitochondrial membrane potential was decreased, and AIF expression was increased in the nucleus (P < 0.01). Reactive oxygen species (ROS) increased gradually within 48 h (P < 0.001). Cathepsin D activities were also increased (P < 0.05). The results demonstrated that the AIF-mediated pathway is a new mitochondrial apoptotic pathway and that mitochondrial depolarization, ROS content, and cathepsin D activities are the key factors influencing apoptosis in GEF cells.
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Affiliation(s)
- Yu-Qing Yan
- College of Life Sciences, Jilin Agricultural University, Changchun, Jilin Province 130118, China
| | - Li-Bo Jin
- Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang Province 325035, China
| | - Yu Wang
- Jilin Academy of Agricultural Sciences, 130033, China
| | - Song-Yan Lu
- Animal Disease Prevention and Control Center of Jilin Province, Changchun, Jilin Province 130062, China
| | - Yi-Feng Pei
- College of Life Sciences, Jilin Agricultural University, Changchun, Jilin Province 130118, China
| | - Dong-Wei Zhu
- College of Life Sciences, Jilin Agricultural University, Changchun, Jilin Province 130118, China
| | - Fu-Sheng Pang
- College of Life Sciences, Jilin Agricultural University, Changchun, Jilin Province 130118, China
| | - Hao Dong
- College of Life Sciences, Jilin Agricultural University, Changchun, Jilin Province 130118, China.
| | - Gui-Xue Hu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, Jilin Province 130118, China.
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Geisler A, Hazini A, Heimann L, Kurreck J, Fechner H. Coxsackievirus B3-Its Potential as an Oncolytic Virus. Viruses 2021; 13:v13050718. [PMID: 33919076 PMCID: PMC8143167 DOI: 10.3390/v13050718] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
Oncolytic virotherapy represents one of the most advanced strategies to treat otherwise untreatable types of cancer. Despite encouraging developments in recent years, the limited fraction of patients responding to therapy has demonstrated the need to search for new suitable viruses. Coxsackievirus B3 (CVB3) is a promising novel candidate with particularly valuable features. Its entry receptor, the coxsackievirus and adenovirus receptor (CAR), and heparan sulfate, which is used for cellular entry by some CVB3 variants, are highly expressed on various cancer types. Consequently, CVB3 has broad anti-tumor activity, as shown in various xenograft and syngeneic mouse tumor models. In addition to direct tumor cell killing the virus induces a strong immune response against the tumor, which contributes to a substantial increase in the efficiency of the treatment. The toxicity of oncolytic CVB3 in healthy tissues is variable and depends on the virus strain. It can be abrogated by genetic engineering the virus with target sites of microRNAs. In this review, we present an overview of the current status of the development of CVB3 as an oncolytic virus and outline which steps still need to be accomplished to develop CVB3 as a therapeutic agent for clinical use in cancer treatment.
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Affiliation(s)
- Anja Geisler
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
| | - Ahmet Hazini
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK;
| | - Lisanne Heimann
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
| | - Jens Kurreck
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
| | - Henry Fechner
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany; (A.G.); (L.H.); (J.K.)
- Correspondence: ; Tel.: +49-30-31-47-21-81
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Jin KT, Du WL, Liu YY, Lan HR, Si JX, Mou XZ. Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements. Cancers (Basel) 2021; 13:cancers13040588. [PMID: 33546172 PMCID: PMC7913179 DOI: 10.3390/cancers13040588] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/26/2021] [Accepted: 01/30/2021] [Indexed: 12/14/2022] Open
Abstract
Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.
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Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China; (K.-T.J.); (Y.-Y.L.)
| | - Wen-Lin Du
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China;
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Yu-Yao Liu
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China; (K.-T.J.); (Y.-Y.L.)
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China;
| | - Jing-Xing Si
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Correspondence: (J.-X.S.); (X.-Z.M.); Tel./Fax: +86-571-85893781 (J.-X.S.); +86-571-85893985 (X.-Z.M.)
| | - Xiao-Zhou Mou
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Correspondence: (J.-X.S.); (X.-Z.M.); Tel./Fax: +86-571-85893781 (J.-X.S.); +86-571-85893985 (X.-Z.M.)
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Mozhei O, G. Teschemacher A, Kasparov S. Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma. Cancers (Basel) 2020; 12:E3724. [PMID: 33322507 PMCID: PMC7764372 DOI: 10.3390/cancers12123724] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 01/02/2023] Open
Abstract
In this review, we scrutinize the idea of using viral vectors either as cytotoxic agents or gene delivery tools for treatment of glioblastoma multiforme (GBM) in light of the experience that our laboratory has accumulated over ~20 years when using similar vectors in experimental neuroscience. We review molecular strategies and current clinical trials and argue that approaches which are based on targeting a specific biochemical pathway or a characteristic mutation are inherently prone to failure because of the high genomic instability and clonal selection characteristics of GBM. For the same reasons, attempts to develop a viral system which selectively transduces only GBM cells are also unlikely to be universally successful. One of the common gene therapy approaches is to use cytotoxic viruses which replicate and cause preferential lysis of the GBM cells. This strategy, in addition to its reliance on the specific biochemical makeup of the GBM cells, bears a risk of necrotic cell death accompanied by release of large quantities of pro-inflammatory molecules. On the other hand, engaging the immune system in the anti-GBM response seems to be a potential avenue to explore further. We suggest that a plausible strategy is to focus on viral vectors which efficiently transduce brain cells via a non-selective, ubiquitous mechanism and which target (ideally irreversibly) processes that are critical only for dividing tumor cells and are dispensable for quiescent brain cells.
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Affiliation(s)
- Oleg Mozhei
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia
| | - Anja G. Teschemacher
- School of Physiology, Neuroscience and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;
| | - Sergey Kasparov
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia
- School of Physiology, Neuroscience and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;
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Rius-Rocabert S, García-Romero N, García A, Ayuso-Sacido A, Nistal-Villan E. Oncolytic Virotherapy in Glioma Tumors. Int J Mol Sci 2020; 21:ijms21207604. [PMID: 33066689 PMCID: PMC7589679 DOI: 10.3390/ijms21207604] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 12/14/2022] Open
Abstract
Glioma tumors are one of the most devastating cancer types. Glioblastoma is the most advanced stage with the worst prognosis. Current therapies are still unable to provide an effective cure. Recent advances in oncolytic immunotherapy have generated great expectations in the cancer therapy field. The use of oncolytic viruses (OVs) in cancer treatment is one such immune-related therapeutic alternative. OVs have a double oncolytic action by both directly destroying the cancer cells and stimulating a tumor specific immune response to return the ability of tumors to escape the control of the immune system. OVs are one promising alternative to conventional therapies in glioma tumor treatment. Several clinical trials have proven the feasibility of using some viruses to specifically infect tumors, eluding undesired toxic effects in the patient. Here, we revisited the literature to describe the main OVs proposed up to the present moment as therapeutic alternatives in order to destroy glioma cells in vitro and trigger tumor destruction in vivo. Oncolytic viruses were divided with respect to the genome in DNA and RNA viruses. Here, we highlight the results obtained in various clinical trials, which are exploring the use of these agents as an alternative where other approaches provide limited hope.
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Affiliation(s)
- Sergio Rius-Rocabert
- Microbiology Section, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, 28668 Madrid, Spain;
- Facultad de Medicina, Instituto de Medicina Molecular Aplicada (IMMA), Universidad San Pablo-CEU, 28668 Madrid, Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, 28668 Madrid, Spain;
| | - Noemí García-Romero
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain;
| | - Antonia García
- Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, 28668 Madrid, Spain;
| | - Angel Ayuso-Sacido
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain;
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
- Correspondence: (A.A.-S.); (E.N.-V.); Tel.: +34-913-724-714 (E.N.-V.)
| | - Estanislao Nistal-Villan
- Microbiology Section, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, 28668 Madrid, Spain;
- Facultad de Medicina, Instituto de Medicina Molecular Aplicada (IMMA), Universidad San Pablo-CEU, 28668 Madrid, Spain
- Correspondence: (A.A.-S.); (E.N.-V.); Tel.: +34-913-724-714 (E.N.-V.)
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Guerrero R, Guerrero C, Acosta O. Induction of Cell Death in the Human Acute Lymphoblastic Leukemia Cell Line Reh by Infection with Rotavirus Isolate Wt1-5. Biomedicines 2020; 8:E242. [PMID: 32722005 PMCID: PMC7460319 DOI: 10.3390/biomedicines8080242] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 06/23/2020] [Indexed: 12/27/2022] Open
Abstract
Cancer is a major health problem that poses a great challenge to health care systems worldwide. Tools for cancer treatment have rapidly advanced in recent years, resulting in therapeutic strategies which are alternative and complementary to conventional treatment. To identify the cell surface receptors used by a tumor cell-adapted rotavirus and the cell death markers induced by its infection, we use Wt1-5, a rotavirus isolate recently adapted to tumor cells, to infect the human acute lymphoblastic leukemia cell line, Reh. The expression of cell surface receptors used by Wt1-5 was determined using flow cytometry and an antibody blocking assay to test for their implication in virus infection. Viral antigens and cell death markers induced by rotavirus infection were followed by flow cytometric analysis. The present study showed that rotavirus Wt1-5 was able to use cell surface proteins such as heat shock proteins (HSPs) 90, 70, 60 and 40, Hsc70, PDI and integrin β3. Rotavirus Wt1-5 induced cytotoxic effects including changes in cell membrane permeability, alteration of mitochondrial membrane potential, DNA fragmentation and activation of cell death signaling. Wt1-5 deserves to be further studied as a candidate oncolytic agent due to its ability to induce apoptosis in lymphoblastic leukemia-derived cells.
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Affiliation(s)
| | - Carlos Guerrero
- Department of Physiological Sciences, Faculty of Medicine, Universidad Nacional de Colombia, Carrera 30 No. 45-03 Bloque 47, Ciudad Universitaria, Bogotá 111321, Colombia; (R.G.); (O.A.)
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Jazowiecka-Rakus J, Sochanik A, Rusin A, Hadryś A, Fidyk W, Villa N, Rahman MM, Chmielik E, Franco LS, McFadden G. Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma. MOLECULAR THERAPY-ONCOLYTICS 2020; 18:335-350. [PMID: 32775618 PMCID: PMC7398944 DOI: 10.1016/j.omto.2020.07.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
Abstract
Oncolytic viruses can target neoplasms, triggering oncolytic and immune effects. Their delivery to melanoma lesions remains challenging. Bone-marrow-derived mesenchymal stem cells (MSCs) were shown to be permissive for oncolytic myxoma virus (MYXV), allowing its transfer to melanoma cells, leading to their killing. Involvement of progeny virus was demonstrated in the transfer from MSCs to co-cultured melanoma cells. The inhibitory effect of virus on melanoma foci formation in murine lungs was revealed using melanoma cells previously co-cultured with MYXV-infected MSCs. Virus accumulation and persistence in lungs of lesion-bearing mice were shown following intravenous administration of MSC-shielded MYXV construct encoding luciferase. Therapy of experimentally induced lung melanoma in mice with interleukin (IL)-15-carrying MYXV construct delivered by MSCs led to marked regression of lesions and could increase survival. Elevated natural killer (NK) cell percentages in blood indicated robust innate responses against unshielded virus only. Lung infiltration by NK cells was followed by inflow of CD8+ T lymphocytes into melanoma lesions. Elevated expression of genes involved in adaptive immune response following oncolytic treatment was confirmed using RT-qPCR. No adverse pathological effects related to MSC-mediated oncolytic therapy with MYXV were observed. MSCs allow for safe and efficient ferrying of therapeutic MYXV to pulmonary melanoma foci triggering immune effects.
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Affiliation(s)
- Joanna Jazowiecka-Rakus
- Maria Skłodowska-Curie Memorial National Research Institute of Oncology, 44-102 Gliwice, Poland
- Corresponding author: Joanna Jazowiecka-Rakus, Maria Skłodowska-Curie Memorial National Research Institute of Oncology, 44-102 Gliwice, Poland.
| | - Aleksander Sochanik
- Maria Skłodowska-Curie Memorial National Research Institute of Oncology, 44-102 Gliwice, Poland
| | - Aleksandra Rusin
- Maria Skłodowska-Curie Memorial National Research Institute of Oncology, 44-102 Gliwice, Poland
| | - Agata Hadryś
- Maria Skłodowska-Curie Memorial National Research Institute of Oncology, 44-102 Gliwice, Poland
| | - Wojciech Fidyk
- Maria Skłodowska-Curie Memorial National Research Institute of Oncology, 44-102 Gliwice, Poland
| | - Nancy Villa
- Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | | | - Ewa Chmielik
- Maria Skłodowska-Curie Memorial National Research Institute of Oncology, 44-102 Gliwice, Poland
| | - Lina S. Franco
- Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Grant McFadden
- Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
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Hartley A, Kavishwar G, Salvato I, Marchini A. A Roadmap for the Success of Oncolytic Parvovirus-Based Anticancer Therapies. Annu Rev Virol 2020; 7:537-557. [PMID: 32600158 DOI: 10.1146/annurev-virology-012220-023606] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autonomous rodent protoparvoviruses (PVs) are promising anticancer agents due to their excellent safety profile, natural oncotropism, and oncosuppressive activities. Viral infection can trigger immunogenic cell death, activating the immune system against the tumor. However, the efficacy of this treatment in recent clinical trials is moderate compared with results seen in preclinical work. Various strategies have been employed to improve the anticancer activities of oncolytic PVs, including development of second-generation parvoviruses with enhanced oncolytic and immunostimulatory activities and rational combination of PVs with other therapies. Understanding the cellular factors involved in the PV life cycle is another important area of investigation. Indeed, these studies may lead to the identification of biomarkers that would allow a more personalized use of PV-based therapies. This review focuses on this work and the challenges that still need to be overcome to move PVs forward into clinical practice as an effective therapeutic option for cancer patients.
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Affiliation(s)
- Anna Hartley
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, 69120 Heidelberg, Germany;
| | - Gayatri Kavishwar
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, 69120 Heidelberg, Germany;
| | - Ilaria Salvato
- Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg;
| | - Antonio Marchini
- Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, 69120 Heidelberg, Germany; .,Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg;
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Zhang Y, Liu Z. Oncolytic Virotherapy for Malignant Tumor: Current Clinical Status. Curr Pharm Des 2020; 25:4251-4263. [PMID: 31682207 DOI: 10.2174/1381612825666191104090544] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022]
Abstract
Oncolytic viruses, as novel biological anti-tumor agents, provide anti-tumor therapeutic effects by different mechanisms including directly selective tumor cell lysis and secondary systemic anti-tumor immune responses. Some wide-type and genetically engineered oncolytic viruses have been applied in clinical trials. Among them, T-Vec has a significant therapeutic effect on melanoma patients and received the approval of the US Food and Drug Administration (FDA) as the first oncolytic virus to treat cancer in the US. However, the mechanisms of virus interaction with tumor and immune systems have not been clearly elucidated and there are still no "gold standards" for instructions of virotherapy in clinical trials. This Review collected the recent clinical trials data from 2005 to summarize the basic oncolytic viruses biology, describe the application in recent clinical trials, and discuss the challenges in the application of oncolytic viruses in clinical trials.
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Affiliation(s)
- Yuhui Zhang
- Department of Spine Surgery, Renji Hospital, Medical School, Shanghai Jiaotong University, Shanghai, China
| | - Zhuoming Liu
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, United States
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Kemp V, Lamfers MLM, van der Pluijm G, van den Hoogen BG, Hoeben RC. Developing oncolytic viruses for clinical use: A consortium approach. Cytokine Growth Factor Rev 2020; 56:133-140. [PMID: 32553482 DOI: 10.1016/j.cytogfr.2020.06.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 06/09/2020] [Indexed: 10/24/2022]
Abstract
The use of oncolytic viruses forms an appealing approach for cancer treatment. On the one hand the viruses replicate in, and kill, tumor cells, leading to their intra-tumoral amplification. On the other hand the viral infection will activate virus-directed immune responses, and may trigger immune responses directed against tumor cells and tumor antigens. To date, a wide variety of oncolytic viruses is being developed for use in cancer treatment. While the development of oncolytic viruses has often been initiated by researchers in academia and other public institutions, a large majority of the final product development and the testing of these products in clinical trials is industry led. As a consequence relatively few pre-clinical and clinical studies evaluated different oncolytic viruses in competitive side-by-side preclinical or clinical studies. In this review we will summarize the steps and considerations essential in the development and characterization of oncolytic viruses, and describe our multidisciplinary academic consortium, which involves a dozen departments in three different Dutch universities, collaborating in the development of oncolytic viruses. This consortium has the ambition to develop a small series of oncolytic viruses and to evaluate these in various cancers.
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Affiliation(s)
- Vera Kemp
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC, Leiden, Netherlands
| | - Martine L M Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, University Medical Center Rotterdam, 3015 CN, Rotterdam, Netherlands
| | - Gabri van der Pluijm
- Department of Urology, Leiden University Medical Center, 2300 RC, Leiden, Netherlands
| | | | - Rob C Hoeben
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC, Leiden, Netherlands.
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Terrível M, Gromicho C, Matos AM. Oncolytic viruses: what to expect from their use in cancer treatment. Microbiol Immunol 2020; 64:477-492. [PMID: 31663631 DOI: 10.1111/1348-0421.12753] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/18/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023]
Abstract
Oncolytic viruses are biologic agents able to selectively infect and destroy cancer cells while sparing the normal ones. Furthermore, they also stimulate the host immune system to combat the tumor growth and to promote tumor removal. This review thoroughly describes different types of viruses developed for targeting specific cancers, as well as the strategies to improve the efficacy and safety of oncolytic virotherapy. It also explores how their potential as anticancer agents may be enhanced through combination with other traditional therapies, such as chemotherapy or more recent approaches, such as checkpoint inhibitors. There are many oncolytic viruses currently being tested in clinical trials for the treatment of various types of cancer, suggesting that this approach could become the near future of the oncology field.
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Affiliation(s)
| | | | - Ana Miguel Matos
- Laboratory of Microbiology, Faculty of Pharmacy, Centre on Chemical Processes Engineering and Forest Products (CIEPQF), University of Coimbra, Portugal
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Emmanuel SN, Mietzsch M, Tseng YS, Smith JK, Agbandje-McKenna M. Parvovirus Capsid-Antibody Complex Structures Reveal Conservation of Antigenic Epitopes Across the Family. Viral Immunol 2020; 34:3-17. [PMID: 32315582 DOI: 10.1089/vim.2020.0022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The parvoviruses are small nonenveloped single stranded DNA viruses that constitute members that range from apathogenic to pathogenic in humans and animals. The infection with a parvovirus results in the generation of antibodies against the viral capsid by the host immune system to eliminate the virus and to prevent re-infection. For members currently either being developed as delivery vectors for gene therapy applications or as oncolytic biologics for tumor therapy, efforts are aimed at combating the detrimental effects of pre-existing or post-treatment antibodies that can eliminate therapeutic benefits. Therefore, understanding antigenic epitopes of parvoviruses can provide crucial information for the development of vaccination applications and engineering novel capsids able to escape antibody recognition. This review aims to capture the information for the binding regions of ∼30 capsid-antibody complex structures of different parvovirus capsids determined to date by cryo-electron microscopy and three-dimensional image reconstruction. The comparison of all complex structures revealed the conservation of antigenic regions among parvoviruses from different genera despite low sequence identity and indicates that the available data can be used across the family for vaccine development and capsid engineering.
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Affiliation(s)
- Shanan N Emmanuel
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Mario Mietzsch
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Yu Shan Tseng
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - James Kennon Smith
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Mavis Agbandje-McKenna
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA
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50
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Li L, Liu S, Han D, Tang B, Ma J. Delivery and Biosafety of Oncolytic Virotherapy. Front Oncol 2020; 10:475. [PMID: 32373515 PMCID: PMC7176816 DOI: 10.3389/fonc.2020.00475] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/16/2020] [Indexed: 12/19/2022] Open
Abstract
In recent years, oncolytic virotherapy has emerged as a promising anticancer therapy. Oncolytic viruses destroy cancer cells, without damaging normal tissues, through virus self-replication and antitumor immunity responses, showing great potential for cancer treatment. However, the clinical guidelines for administering oncolytic virotherapy remain unclear. Delivery routes for oncolytic virotherapy to patients vary in existing studies, depending on the tumor sites and the objective of studies. Moreover, the biosafety of oncolytic virotherapy, including mainly uncontrolled adverse events and long-term complications, remains a serious concern that needs to be accurately measured. This review provides a comprehensive and detailed overview of the delivery and biosafety of oncolytic virotherapy.
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Affiliation(s)
- Lizhi Li
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Shixin Liu
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Duoduo Han
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Bin Tang
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Jian Ma
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, National Health Commission Key Laboratory of Carcinogenesis, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, China
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