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James JS, Dai J, Chew WL, Cai Y. The design and engineering of synthetic genomes. Nat Rev Genet 2025; 26:298-319. [PMID: 39506144 DOI: 10.1038/s41576-024-00786-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2024] [Indexed: 11/08/2024]
Abstract
Synthetic genomics seeks to design and construct entire genomes to mechanistically dissect fundamental questions of genome function and to engineer organisms for diverse applications, including bioproduction of high-value chemicals and biologics, advanced cell therapies, and stress-tolerant crops. Recent progress has been fuelled by advancements in DNA synthesis, assembly, delivery and editing. Computational innovations, such as the use of artificial intelligence to provide prediction of function, also provide increasing capabilities to guide synthetic genome design and construction. However, translating synthetic genome-scale projects from idea to implementation remains highly complex. Here, we aim to streamline this implementation process by comprehensively reviewing the strategies for design, construction, delivery, debugging and tailoring of synthetic genomes as well as their potential applications.
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Affiliation(s)
- Joshua S James
- Manchester Institute of Biotechnology, University of Manchester, Manchester, UK
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Junbiao Dai
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Shenzhen Key Laboratory of Agricultural Synthetic Biology, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Wei Leong Chew
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Yizhi Cai
- Manchester Institute of Biotechnology, University of Manchester, Manchester, UK.
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2
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West EJ, Sadoun A, Bendjama K, Erbs P, Smolenschi C, Cassier PA, de Baere T, Sainte-Croix S, Brandely M, Melcher AA, Ismail F, Scott KJ, Bennett A, Banks E, Gasior E, Kent S, Kurzawa M, Hammond C, Patel JV, Collinson FJ, Twelves C, Anthoney DA, Swinson D, Samson A. A Phase I Clinical Trial of Intrahepatic Artery Delivery of TG6002 in Combination with Oral 5-Fluorocytosine in Patients with Liver-Dominant Metastatic Colorectal Cancer. Clin Cancer Res 2025; 31:1243-1256. [PMID: 39785814 PMCID: PMC11959272 DOI: 10.1158/1078-0432.ccr-24-2498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/30/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
PURPOSE Effective treatment for patients with metastatic cancer is limited, particularly for those with colorectal cancer with metastatic liver lesions, in which accessibility to numerous tumors is essential for favorable clinical outcomes. Oncolytic viruses (OV) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoral administration routes. PATIENTS AND METHODS We conducted a multicenter, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral prodrug 5-fluorocytosine to 15 patients with metastatic colorectal cancer. RESULTS Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by the virus within tumor biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumor, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to the virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T-cell receptor clones against both cancer antigens and neoantigens, with elevated functional activity, may be associated with improved anticancer activity. Despite these findings, no clinical efficacy was observed. CONCLUSIONS In summary, these data demonstrate the delivery of OV to tumor via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data support the need for future studies using IHA administration of OVs.
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Affiliation(s)
- Emma J. West
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
| | | | | | | | | | | | | | | | | | | | - Fay Ismail
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
| | - Karen J. Scott
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
| | - Angela Bennett
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Emma Banks
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Ewa Gasior
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Sarah Kent
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Marta Kurzawa
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | | | - Jai V. Patel
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Fiona J. Collinson
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Chris Twelves
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - D. Alan Anthoney
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Dan Swinson
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Adel Samson
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
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3
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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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4
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Valouzi A, Shahbazi M, Erfani-Moghadam V, Ramezani M, Shamsabadi FT. Cancer-Specific Activation of the Vesicular Stomatitis Virus Matrix by Survivin Promoter in Breast Cancer Cells. Mol Biotechnol 2025:10.1007/s12033-024-01359-4. [PMID: 39820852 DOI: 10.1007/s12033-024-01359-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
Oncolytic viral-based therapy and specific gene expression by promoters are modern targeted oncotherapy approaches that have gained significant attention in recent years. In this study, both strategies were combined by designing cancer-specific activation of vesicular stomatitis virus matrix expression under the survivin promoter. The matrix sequence was cloned downstream of the survivin promoter (pM). After transfecting MCF-7 cells with pM, cell proliferation and apoptosis induction were assessed. Additionally, the transcript levels of matrix and apoptosis-related genes in response to pM was assessed. The proliferation of MCF-7 cells was significantly reduced by the constructed matrix-expressing plasmid at 48 and 72 h post-transfection (p < 0.05). Enhanced matrix expression resulted in the down-regulation of MMP-9, TP53, and NF-kB, while simultaneously up-regulating Bax transcripts. Evaluating the effect of pM vector on apoptosis induction revealed a significant increase in the MCF-7 cells compared to untreated cells (p < 0.05). The absence of significant matrix gene expression in HDF cells, relative to MCF-7 cells, further underscores the specific function of the Survivin promoter in cancer cells. These findings suggest that the matrix may have various biological functions in a diverse set of non-apoptotic pathways. Further research on the association of the matrix with other genes could provide insights into the biomedical significance and future perspectives of the matrix in cancer gene therapy.
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Affiliation(s)
- Atefeh Valouzi
- Department of Medical Biotechnology, Golestan University of Medical Sciences, Gorgan, Iran
- Medical Cellular & Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Department of Medical Biotechnology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Vahid Erfani-Moghadam
- Department of Medical Biotechnology, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mahboobeh Ramezani
- Medical Cellular & Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Fatemeh T Shamsabadi
- Department of Medical Biotechnology, Golestan University of Medical Sciences, Gorgan, Iran.
- Medical Cellular & Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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5
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Glaschke S, Dobrovolny HM. Spatiotemporal spread of oncolytic virus in a heterogeneous cell population. Comput Biol Med 2024; 183:109235. [PMID: 39369544 DOI: 10.1016/j.compbiomed.2024.109235] [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: 07/12/2024] [Revised: 09/27/2024] [Accepted: 09/30/2024] [Indexed: 10/08/2024]
Abstract
Oncolytic (cancer-killing) virus treatment is a promising new therapy for cancer, with many viruses currently being tested for their ability to eradicate tumors. One of the major stumbling blocks to the development of this treatment modality has been preventing spread of the virus to non-cancerous cells. Our recent ability to manipulate RNA and DNA now allows for the possibility of creating designer viruses specifically targeted to cancer cells, thereby significantly reducing unwanted side effects in patients. In this study, we use a partial differential equation model to determine the characteristics of a virus needed to contain spread of an oncolytic virus within a spherical tumor and prevent it from spreading to non-cancerous cells outside the tumor. We find that oncolytic viruses that have different infection rates or different cell death rates in cancer and non-cancerous cells can be made to stay within the tumor. We find that there is a minimum difference in infection rates or cell death rates that will contain the virus and that this threshold value depends on the growth rate of the cancer. Identification of these types of thresholds can help researchers develop safer strains of oncolytic viruses allowing further development of this promising treatment.
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Affiliation(s)
- Sabrina Glaschke
- Institute of Physics, Universitat Kassel, Kassel, Germany; Department of Physics & Astronomy, Texas Christian University, Fort Worth, TX, USA
| | - Hana M Dobrovolny
- Department of Physics & Astronomy, Texas Christian University, Fort Worth, TX, USA.
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6
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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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7
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Omole AO, Zhao Z, Chang-Liao S, de Oliveira JFA, Boone CE, Sutorus L, Sack M, Varner J, Fiering SN, Steinmetz NF. Virus nanotechnology for intratumoural immunotherapy. NATURE REVIEWS BIOENGINEERING 2024; 2:916-929. [PMID: 39698315 PMCID: PMC11655125 DOI: 10.1038/s44222-024-00231-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/22/2024] [Indexed: 12/20/2024]
Abstract
Viruses can be designed to be tools and carrier vehicles for intratumoural immunotherapy. Their nanometre-scale size and shape allow for functionalization with or encapsulation of medical cargoes and tissue-specific ligands. Importantly, immunotherapies may particularly benefit from the inherent immunomodulatory properties of viruses. For example, mammalian viruses have already been tested for oncolytic virotherapy, and bacteriophages and plant viruses can be engineered for immunotherapeutic treatment approaches. In this Review, we discuss how viruses - including oncolytic viruses, immunomodulatory plant viruses and bacteriophages - and virus-like particles can be designed for intratumoural immunotherapy to elicit anti-tumour immunity and induce systemic anti-tumour responses at distant non-injected sites. We further highlight the engineering of viruses and virus-like particles as drug-delivery systems, and outline key translational challenges and clinical opportunities.
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Affiliation(s)
- Anthony O. Omole
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Zhongchao Zhao
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Sabrina Chang-Liao
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Jessica Fernanda Affonso de Oliveira
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Christine E. Boone
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Lucas Sutorus
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | | | - Judith Varner
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Center for Engineering in Cancer, Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - Steven N. Fiering
- Department of Microbiology and Immunology, Dartmouth Cancer Center, Dartmouth Geisel School of Medicine and Dartmouth-Hitchock Health, Lebanon, NH, USA
| | - Nicole F. Steinmetz
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Center for Engineering in Cancer, Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Radiology, University of California, San Diego, La Jolla, CA, USA
- Institute for Materials Discovery and Design, University of California, San Diego, La Jolla, CA, USA
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8
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Hamilton JR, Chen E, Perez BS, Sandoval Espinoza CR, Kang MH, Trinidad M, Ngo W, Doudna JA. In vivo human T cell engineering with enveloped delivery vehicles. Nat Biotechnol 2024; 42:1684-1692. [PMID: 38212493 PMCID: PMC11236958 DOI: 10.1038/s41587-023-02085-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/01/2023] [Indexed: 01/13/2024]
Abstract
Viruses and virally derived particles have the intrinsic capacity to deliver molecules to cells, but the difficulty of readily altering cell-type selectivity has hindered their use for therapeutic delivery. Here, we show that cell surface marker recognition by antibody fragments displayed on membrane-derived particles encapsulating CRISPR-Cas9 protein and guide RNA can deliver genome editing tools to specific cells. Compared to conventional vectors like adeno-associated virus that rely on evolved capsid tropisms to deliver virally encoded cargo, these Cas9-packaging enveloped delivery vehicles (Cas9-EDVs) leverage predictable antibody-antigen interactions to transiently deliver genome editing machinery selectively to cells of interest. Antibody-targeted Cas9-EDVs preferentially confer genome editing in cognate target cells over bystander cells in mixed populations, both ex vivo and in vivo. By using multiplexed targeting molecules to direct delivery to human T cells, Cas9-EDVs enable the generation of genome-edited chimeric antigen receptor T cells in humanized mice, establishing a programmable delivery modality with the potential for widespread therapeutic utility.
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Affiliation(s)
- Jennifer R Hamilton
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
- Azalea Therapeutics, Berkeley, CA, USA
| | - Evelyn Chen
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
- Azalea Therapeutics, Berkeley, CA, USA
| | - Barbara S Perez
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Cindy R Sandoval Espinoza
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Min Hyung Kang
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Marena Trinidad
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Wayne Ngo
- Gladstone Institutes, San Francisco, CA, USA
- California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA
| | - Jennifer A Doudna
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
- Innovative Genomics Institute, University of California, Berkeley, CA, USA.
- Gladstone Institutes, San Francisco, CA, USA.
- California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, USA.
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
- Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
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9
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Zhang G, Wang Q, Yuan R, Zhang Y, Chen K, Yu J, Ye T, Jia X, Zhou Y, Li G, Chen K. Oncolytic vaccinia virus harboring aphrocallistes vastus lectin exerts anti-tumor effects by directly oncolysis and inducing immune response through enhancing ROS in human ovarian cancer. Biochem Biophys Res Commun 2024; 730:150355. [PMID: 38996784 DOI: 10.1016/j.bbrc.2024.150355] [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: 06/27/2024] [Accepted: 07/04/2024] [Indexed: 07/14/2024]
Abstract
Aphrocallistes vastus lectin (AVL) is a Ca2+ dependent C-type lectin produced by sponges. Previous studies have demonstrated that oncolytic vaccinia virus harboring AVL (oncoVV-AVL) effectively triggers cell death in various tumors. However, the effects of oncoVV-AVL on human ovarian cancer (OV) remain unknown. This study aims to investigate the mechanism-of-action of oncoVV-AVL in human OV cell lines and in tumor-bearing nude mice. We found that oncoVV-AVL could directly induce apoptosis and autophagy in ovarian cancer cells. Additionally, our results showed that oncoVV-AVL increased the serum levels of mouse IFN-γ (mIFN-γ), leading to the activation of M1-polarized macrophages. Conversely, NADPH, a reducing agent by providing reducing equivalents, reduced the production of mIFN-γ, and suppressed M1-polarization of macrophage. Based on these findings, we propose that oncoVV-AVL not only contributes to direct cytolysis, but also enhances host immune response by promoting ROS levels.
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Affiliation(s)
- Guohui Zhang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Qiang Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Rentao Yuan
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yanan Zhang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Ke Chen
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Jianlei Yu
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Ting Ye
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xiaoyuan Jia
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yanrong Zhou
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Gongchu Li
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China; Hangzhou Gongchu Biotechnology Co., Ltd., Hangzhou, China.
| | - Kan Chen
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
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10
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Yang Z, Chen L, Guo T, Huang L, Yang Y, Ye R, Zhang Y, Lin X, Fan Y, Gong C, Yang N, Guan W, Liang D, Ouyang W, Yang W, Zhao X, Zhang J. Cationic liposomes overcome neutralizing antibodies and enhance reovirus efficacy in ovarian cancer. Virology 2024; 598:110196. [PMID: 39098183 DOI: 10.1016/j.virol.2024.110196] [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: 05/01/2024] [Revised: 07/16/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
Reovirus (Reo) has shown promising potential in specifically killing tumor cells, and offering new possibilities for ovarian cancer (OC) treatment. However, neutralizing antibodies in the ascites from OC patients greatly limit the further application of Reo. In this study, we employed cationic liposomes (Lipo) to deliver Reo, significantly enhancing its ability to enter OC cells and its effectiveness in killing these cells under ascitic conditions. Pre-treatment with the MβCD inhibitor notably decreased Reo-mediated tumor cell death, indicating that Lipo primarily enables Reo's cellular uptake through caveolin-mediated endocytosis. Our results demonstrate that Lipo effectively facilitates the entry of Reo into the cytoplasm and triggers cell apoptosis. The above findings provide a new strategy to overcome the obstacle of neutralizing antibodies in the clinical application of Reo.
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Affiliation(s)
- Zhiru Yang
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Liang Chen
- Department of Thoracic and Breast Surgery, Anshun People's Hospital, Anshun, Guizhou, China
| | - Ting Guo
- Department of Gynecology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Lei Huang
- Department of Thoracic and Breast Surgery, Anshun People's Hospital, Anshun, Guizhou, China
| | - Yuxin Yang
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Rui Ye
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yingchun Zhang
- Department of Biology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China; Tumor Immunotherapy Technology Engineering Research Center, Guizhou Medical University, Guiyang, Guizhou, China
| | - Xiaojin Lin
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Biology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yuting Fan
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China; Department of Gastroenterology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Chulan Gong
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Na Yang
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Weili Guan
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Biology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Dan Liang
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Weiwei Ouyang
- Department of Thoracic Oncology, The Affiliated Hospital/The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, China
| | - Wei Yang
- Department of Oncology, Guizhou Medical University, Guiyang, China
| | - Xing Zhao
- Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University (GMU), Guiyang, Guizhou, China; Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China; Tumor Immunotherapy Technology Engineering Research Center, Guizhou Medical University, Guiyang, Guizhou, China.
| | - Jing Zhang
- Department of Biology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.
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11
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Robinson SI, Rochell RE, Penza V, Naik S. Translation of oncolytic viruses in sarcoma. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200822. [PMID: 39040851 PMCID: PMC11261849 DOI: 10.1016/j.omton.2024.200822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Sarcomas are a rare and highly diverse group of malignancies of mesenchymal origin. While sarcomas are generally considered resistant to immunotherapy, recent studies indicate subtype-specific differences in clinical response to checkpoint inhibitors (CPIs) that are associated with distinct immune phenotypes present in sarcoma subtypes. Oncolytic viruses (OVs) are designed to selectively infect and kill tumor cells and induce intratumoral immune infiltration, enhancing immunogenicity and thereby sensitizing tumors to immunotherapy. Herein we review the accumulated clinical data evaluating OVs in sarcoma. Small numbers of patients with sarcoma were enrolled in early-stage OV trials as part of larger solid tumor cohorts demonstrating safety but providing limited insight into the biological effects due to the low patient numbers and lack of histologic grouping. Several recent studies have investigated talimogene laherparepvec (T-VEC), an approved oncolytic herpes simplex virus (HSV-1), in combination therapy regimens in sarcoma patient cohorts. These studies have shown promising responses in heavily pre-treated and immunotherapy-resistant patients associated with increased intratumoral immune infiltration. As new and more potent OVs enter the clinical arena, prospective evaluation in subtype-specific cohorts with correlative studies to define biomarkers of response will be critical to advancing this promising approach for sarcoma therapy.
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Affiliation(s)
- Steven I. Robinson
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55902, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Roya E. Rochell
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Velia Penza
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Shruthi Naik
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
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12
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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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13
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Kiaheyrati N, Babaei A, Ranji R, Bahadoran E, Taheri S, Farokhpour Z. Cancer therapy with the viral and bacterial pathogens: The past enemies can be considered the present allies. Life Sci 2024; 349:122734. [PMID: 38788973 DOI: 10.1016/j.lfs.2024.122734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024]
Abstract
Cancer continues to be one of the leading causes of mortality worldwide despite significant advancements in cancer treatment. Many difficulties have arisen as a result of the detrimental consequences of chemotherapy and radiotherapy as a common cancer therapy, such as drug inability to penetrate deep tumor tissue, and also the drug resistance in tumor cells continues to be a major concern. These obstacles have increased the need for the development of new techniques that are more selective and effective against cancer cells. Bacterial-based therapies and the use of oncolytic viruses can suppress cancer in comparison to other cancer medications. The tumor microenvironment is susceptible to bacterial accumulation and proliferation, which can trigger immune responses against the tumor. Oncolytic viruses (OVs) have also gained considerable attention in recent years because of their potential capability to selectively target and induce apoptosis in cancer cells. This review aims to provide a comprehensive summary of the latest literature on the role of bacteria and viruses in cancer treatment, discusses the limitations and challenges, outlines various strategies, summarizes recent preclinical and clinical trials, and emphasizes the importance of optimizing current strategies for better clinical outcomes.
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Affiliation(s)
- Niloofar Kiaheyrati
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Abouzar Babaei
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran.
| | - Reza Ranji
- Department of Genetics, Faculty of Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ensiyeh Bahadoran
- School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Shiva Taheri
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zahra Farokhpour
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
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14
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Chattopadhyay S, Hazra R, Mallick A, Gayen S, Roy S. A review exploring the fusion of oncolytic viruses and cancer immunotherapy: An innovative strategy in the realm of cancer treatment. Biochim Biophys Acta Rev Cancer 2024; 1879:189110. [PMID: 38754793 DOI: 10.1016/j.bbcan.2024.189110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/18/2024]
Abstract
Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy cells. They enhance antitumor immunity by triggering various immune responses throughout the cancer cycle. Genetically engineered OVs swiftly destroy cancerous tissues and activate the immune system by releasing soluble antigens like danger signals and interferons. Their ability to stimulate both innate and adaptive immunity makes them particularly attractive in cancer immunotherapy. Recent advancements involve combining OVs with other immune therapies, yielding promising results. Transgenic OVs, designed to enhance immunostimulation and specifically target cancer cells, further improve immune responses. This review highlights the intrinsic mechanisms of OVs and underscores their synergistic potential with other immunotherapies. It also proposes strategies for optimizing armed OVs to bolster immunity against tumors.
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Affiliation(s)
- Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India.
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15
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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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16
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Nia GE, Nikpayam E, Farrokhi M, Bolhassani A, Meuwissen R. Advances in cell-based delivery of oncolytic viruses as therapy for lung cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200788. [PMID: 38596310 PMCID: PMC10976516 DOI: 10.1016/j.omton.2024.200788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Lung cancer's intractability is enhanced by its frequent resistance to (chemo)therapy and often high relapse rates that make it the leading cause of cancer death worldwide. Improvement of therapy efficacy is a crucial issue that might lead to a significant advance in the treatment of lung cancer. Oncolytic viruses are desirable combination partners in the developing field of cancer immunotherapy due to their direct cytotoxic effects and ability to elicit an immune response. Systemic oncolytic virus administration through intravenous injection should ideally lead to the highest efficacy in oncolytic activity. However, this is often hampered by the prevalence of host-specific, anti-viral immune responses. One way to achieve more efficient systemic oncolytic virus delivery is through better protection against neutralization by several components of the host immune system. Carrier cells, which can even have innate tumor tropism, have shown their appropriateness as effective vehicles for systemic oncolytic virus infection through circumventing restrictive features of the immune system and can warrant oncolytic virus delivery to tumors. In this overview, we summarize promising results from studies in which carrier cells have shown their usefulness for improved systemic oncolytic virus delivery and better oncolytic virus therapy against lung cancer.
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Affiliation(s)
- Giti Esmail Nia
- Faculty of Allied Medicine, Cellular and Molecular Research Centre, Iran University of Medical Science, Tehran, Iran
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
| | - Elahe Nikpayam
- Department of Regenerative and Cancer Biology, Albany Medical College, Albany, NY, USA
| | | | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Ralph Meuwissen
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
- Ege University Translational Pulmonary Research Center (EgeSAM), Ege University, Izmir, Turkey
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17
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Joo HY, Baek H, Ahn CS, Park ER, Lee Y, Lee S, Han M, Kim B, Jang YH, Kwon H. Development of a novel, high-efficacy oncolytic herpes simplex virus type 1 platform equipped with two distinct retargeting modalities. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200778. [PMID: 38596302 PMCID: PMC10941007 DOI: 10.1016/j.omton.2024.200778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 01/03/2024] [Accepted: 02/16/2024] [Indexed: 04/11/2024]
Abstract
To retarget oncolytic herpes simplex virus (oHSV) to cancer-specific antigens, we designed a novel, double-retargeted oHSV platform that uses single-chain antibodies (scFvs) incorporated into both glycoprotein H and a bispecific adapter expressed from the viral genome to mediate infection predominantly via tumor-associated antigens. Successful retargeting was achieved using a nectin-1-detargeted HSV that remains capable of interacting with herpesvirus entry mediator (HVEM), the second canonical HSV entry receptor, and is, therefore, recognized by the adapter consisting of the virus-binding N-terminal 82 residues of HVEM fused to the target-specific scFv. We tested both an epithelial cell adhesion molecule (EpCAM)- and a human epidermal growth factor receptor 2-specific scFv separately and together to target cells expressing one, the other, or both receptors. Our results show not only dose-dependent, target receptor-specific infection in vitro, but also enhanced virus spread compared with single-retargeted virus. In addition, we observed effective infection and spreading of the EpCAM double-retargeted virus in vivo. Remarkably, a single intravenous dose of the EpCAM-specific virus eliminated all detectable tumors in a subcutaneous xenograft model, and the same intravenous dose seemed to be harmless in immunocompetent FVB/N mice. Our findings suggest that our double-retargeted oHSV platform can provide a potent, versatile, and systemically deliverable class of anti-cancer therapeutics that specifically target cancer cells while ensuring safety.
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Affiliation(s)
- Hyun-Yoo Joo
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Hyunjung Baek
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Chun-Seob Ahn
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Eun-Ran Park
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Youngju Lee
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Sujung Lee
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Mihee Han
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Bora Kim
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Yong-Hoon Jang
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
| | - Heechung Kwon
- Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
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18
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Volovat SR, Scripcariu DV, Vasilache IA, Stolniceanu CR, Volovat C, Augustin IG, Volovat CC, Ostafe MR, Andreea-Voichița SG, Bejusca-Vieriu T, Lungulescu CV, Sur D, Boboc D. Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy. Int J Mol Sci 2024; 25:1180. [PMID: 38256250 PMCID: PMC10816814 DOI: 10.3390/ijms25021180] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.
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Affiliation(s)
- Simona Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Dragos Viorel Scripcariu
- Department of Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Ingrid Andrada Vasilache
- Department of Obstetrics and Gynecology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics—Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Constantin Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | | | - Madalina-Raluca Ostafe
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Slevoacă-Grigore Andreea-Voichița
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Toni Bejusca-Vieriu
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | - Daniel Sur
- 11th Department of Medical Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania;
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
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19
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Jung BK, An YH, Jang SH, Jang JJ, Kim S, Jeon JH, Kim J, Song JJ, Jang H. The artificial amino acid change in the sialic acid-binding domain of the hemagglutinin neuraminidase of newcastle disease virus increases its specificity to HCT 116 colorectal cancer cells and tumor suppression effect. Virol J 2024; 21:7. [PMID: 38178138 PMCID: PMC10768451 DOI: 10.1186/s12985-023-02276-9] [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: 10/30/2023] [Accepted: 12/22/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Oncolytic viruses are being studied and developed as novel cancer treatments. Using directed evolution technology, structural modification of the viral surface protein increases the specificity of the oncolytic virus for a particular cancer cell. Newcastle disease virus (NDV) does not show specificity for certain types of cancer cells during infection; therefore, it has low cancer cell specificity. Hemagglutinin is an NDV receptor-binding protein on the cell surface that determines host cell tropism. NDV selectivity for specific cancer cells can be increased by artificial amino acid changes in hemagglutinin neuraminidase HN proteins via directed evolution, leading to improved therapeutic effects. METHODS Sialic acid-binding sites (H domains) of the HN protein mutant library were generated using error-prone PCR. Variants of the H domain protein were screened by enzyme-linked immunosorbent assay using HCT 116 cancer cell surface molecules. The mutant S519G H domain protein showed the highest affinity for the surface protein of HCT 116 cells compared to that of different types of cancer cells. This showed that the S519G mutant H domain protein gene replaced the same part of the original HN protein gene, and S519G mutant recombinant NDV (rNDV) was constructed and recovered. S519G rNDV cancer cell killing effects were tested using the MTT assay with various cancer cell types, and the tumor suppression effect of the S519G mutant rNDV was tested in a xenograft mouse model implanted with cancer cells, including HCT 116 cells. RESULTS S519G rNDV showed increased specificity and enhanced killing ability of HCT 116 cells among various cancer cells and a stronger suppressive effect on tumor growth than the original recombinant NDV. Directed evolution using an artificial amino acid change in the NDV HN (S519G mutant) protein increased its specificity and oncolytic effect in colorectal cancer without changing its virulence. CONCLUSION These results provide a new methodology for the use of directed evolution technology for more effective oncolytic virus development.
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Affiliation(s)
| | - Yong Hee An
- Libentech Co. LTD, Daejeon, Republic of Korea
| | - Sung Hoon Jang
- Graduate School of Medical Science, College of medicine, Yonsei University, Seoul, Republic of Korea
| | - Jin-Ju Jang
- Libentech Co. LTD, Daejeon, Republic of Korea
| | - Seonhee Kim
- Libentech Co. LTD, Daejeon, Republic of Korea
| | | | - Jinju Kim
- Libentech Co. LTD, Daejeon, Republic of Korea
| | - Jason Jungsik Song
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea
- Institute for Immunology and Immunological Disease, College of Medicine, Yonsei University, Seoul, Korea
| | - Hyun Jang
- Libentech Co. LTD, Daejeon, Republic of Korea.
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20
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E VB, Ranganath Pai KS. Stem Cells and Tumor-Killing Virus to Target Brain Tumor: In Pursuit to Bring a Potential Delivery Vehicle for the Central Nervous System Tumors. Curr Drug Deliv 2024; 21:2-15. [PMID: 36825709 DOI: 10.2174/1567201820666230220101052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 12/08/2022] [Accepted: 12/28/2022] [Indexed: 02/22/2023]
Abstract
To target brain cancer, various therapeutic options are present to fight against cancer cells. But the existing therapies are not showing a proper curation of cancer patients. Henceforth, activating the immune cells and targeting oncogenes/proteins might be an emerging therapeutic approach to target and destroy malignant brain tumor. Stem cells (SCs) are considered potential immunomodulators that trigger the highly suppressed immune system in the tumor microenvironment. Also, engineered SCs can repress the aberrantly expressed oncoproteins that cause tumor cell proliferation and growth. SCs have an excellent migration capability to reach the infected site and support the regeneration of damaged blood vessels and tissues. Likewise, oncolytic virotherapy (OVT) is a promising novel therapeutic molecule in which genetically modified viruses can selectively replicate and destroy cancer cells without harming healthy cells. Same as SCs, oncolytic viruses (OVs) tend to stimulate the host's innate and adaptive immune response to battle against the advanced brain tumor. In clinical studies, various OVs have shown good immunogenic responses with a high safety profile and tolerability against cancer patients with reduced morbidity and mortality rate. SCs act as an attractive cargo for OVs which helps to influence the tumor site and destroy the tumor volume. SCs protect the OVs from systemic degradation and promote therapeutic efficacy against cancer cells. SCs carried OVs might be a potential therapeutic way to bring an effective treatment option for brain tumors.
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Affiliation(s)
- Vignesh Balaji E
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
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21
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Chakraborty P, Kumar R, Karn S, Raviya DD, Mondal P. Application of Oncolytic Poxviruses: An Emerging Paradigm in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1451:369-381. [PMID: 38801591 DOI: 10.1007/978-3-031-57165-7_24] [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: 05/29/2024]
Abstract
Despite the significant advancement of new tools and technology in the field of medical biology and molecular biology, the challenges in the treatment of most cancer types remain constant with the problem of developing resistance toward drugs and no substantial enhancement in the overall survival rate of cancer patients. Immunotherapy has shown the most promising results in different clinical and preclinical trials in the treatment of various cancer due to its higher efficacy and minimum collateral damage in many cancer patients as compared to conventional chemotherapy and radiotherapy. An oncolytic virus is a new class of immunotherapy that can selectively replicate in tumor cells and destroy them by the process of cell lysis while exerting minimum or no effect on a normal cell. Besides this, it can also activate the host's innate immune system, which generates an anti-tumor immune response to eliminate the tumor cells. Several wild types and genetically modified viruses have been investigated to show oncolytic behavior. Vaccinia virus has been studied extensively and tested for its promising oncolytic nature on various model systems and clinical trials. Recently, several engineered vaccinia viruses have been developed that express the desired genes encoded for selective penetration in tumor cells and enhanced activation of the immune system for generating anti-tumor immunity. However, further investigation is required to prove their potential and enhance their therapeutic efficacy.
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Affiliation(s)
- Prasenjit Chakraborty
- Department of Biosciences, School of Science, Indrashil University, Rajpur-Kadi, Mehsana, Gujarat, 382740, India.
| | - Randhir Kumar
- Department of Biosciences, School of Science, Indrashil University, Rajpur-Kadi, Mehsana, Gujarat, 382740, India
| | - Sanjay Karn
- Department of Biosciences, School of Science, Indrashil University, Rajpur-Kadi, Mehsana, Gujarat, 382740, India
| | - Dharmiben D Raviya
- Department of Biosciences, School of Science, Indrashil University, Rajpur-Kadi, Mehsana, Gujarat, 382740, India
| | - Priya Mondal
- Laboratory of Cell Biology, National Cancer Institute, National Institute of Health, Bethesda, MD, 20892, USA
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22
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Al-Shammari AM, Piccaluga PP. Editorial: Oncolytic virotherapy. Front Mol Biosci 2023; 10:1287885. [PMID: 38028532 PMCID: PMC10646606 DOI: 10.3389/fmolb.2023.1287885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 10/04/2023] [Indexed: 12/01/2023] Open
Affiliation(s)
- Ahmed Majeed Al-Shammari
- Experimental Therapy Department, Iraqi Center for Cancer and Medical Genetic Research, Mustansiriyah University, Baghdad, Iraq
| | - Pier Paolo Piccaluga
- Biobank of Research, IRCCS Azienda Opedaliera-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Bologna University School of Medicine, Bologna, Italy
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23
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Nayak V, Patra S, Singh KR, Ganguly B, Kumar DN, Panda D, Maurya GK, Singh J, Majhi S, Sharma R, Pandey SS, Singh RP, Kerry RG. Advancement in precision diagnosis and therapeutic for triple-negative breast cancer: Harnessing diagnostic potential of CRISPR-cas & engineered CAR T-cells mediated therapeutics. ENVIRONMENTAL RESEARCH 2023; 235:116573. [PMID: 37437865 DOI: 10.1016/j.envres.2023.116573] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/29/2023] [Accepted: 07/06/2023] [Indexed: 07/14/2023]
Abstract
Cancer is characterized by uncontrolled cell growth, disrupted regulatory pathways, and the accumulation of genetic mutations. These mutations across different types of cancer lead to disruptions in signaling pathways and alterations in protein expression related to cellular growth and proliferation. This review highlights the AKT signaling cascade and the retinoblastoma protein (pRb) regulating cascade as promising for novel nanotheranostic interventions. Through synergizing state-of-the-art gene editing tools like the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas system with nanomaterials and targeting AKT, there is potential to enhance cancer diagnostics significantly. Furthermore, the integration of modified CAR-T cells into multifunctional nanodelivery systems offers a promising approach for targeted cancer inhibition, including the eradication of cancer stem cells (CSCs). Within the context of highly aggressive and metastatic Triple-negative Breast Cancer (TNBC), this review specifically focuses on devising innovative nanotheranostics. For both pre-clinical and post-clinical TNBC detection, the utilization of the CRISPR-Cas system, guided by RNA (gRNA) and coupled with a fluorescent reporter specifically designed to detect TNBC's mutated sequence, could be promising. Additionally, a cutting-edge approach involving the engineering of TNBC-specific iCAR and syn-Notch CAR T-cells, combined with the co-delivery of a hybrid polymeric nano-liposome encapsulating a conditionally replicative adenoviral vector (CRAdV) against CSCs, could present an intriguing intervention strategy. This review thus paves the way for exciting advancements in the field of nanotheranostics for the treatment of TNBC and beyond.
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Affiliation(s)
- Vinayak Nayak
- Indian Council of Agricultural Research- National Institute on Foot and Mouth Disease- International Center for Foot and Mouth Disease, Bhubaneswar, Odisha, India
| | - Sushmita Patra
- Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi-Mumbai 410210, India
| | - Kshitij Rb Singh
- Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu, Kitakyushu, Japan.
| | - Bristy Ganguly
- Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar, Odisha, India
| | - Das Nishant Kumar
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India
| | - Deepak Panda
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India
| | - Ganesh Kumar Maurya
- Zoology Section, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Jay Singh
- Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sanatan Majhi
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Shyam S Pandey
- Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu, Kitakyushu, Japan.
| | - Ravindra Pratap Singh
- Department of Biotechnology, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India.
| | - Rout George Kerry
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India.
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24
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Noraldeen SAM, Rasulova I, Lalitha R, Hussin F, Alsaab HO, Alawadi AH, Alsaalamy A, Sayyid NH, Alkhafaji AT, Mustafa YF, Shayan SK. Involving stemness factors to improve CAR T-cell-based cancer immunotherapy. Med Oncol 2023; 40:313. [PMID: 37779152 DOI: 10.1007/s12032-023-02191-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/09/2023] [Indexed: 10/03/2023]
Abstract
Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.
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Affiliation(s)
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, 54 Mustaqillik Ave., 100007, Tashkent, Uzbekistan
| | - Repudi Lalitha
- Department of Pharmaceutical Analysis, Chaitanya Deemed to be University, Hyderabad, Telangana, India.
| | - Farah Hussin
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, 21944, Taif, Saudi Arabia
| | - Ahmed Hussien Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
| | - Nidhal Hassan Sayyid
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sepideh Karkon Shayan
- Student Research Committee, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
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25
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Robilotti E, Zeitouni NC, Orloff M. Biosafety and biohazard considerations of HSV-1-based oncolytic viral immunotherapy. Front Mol Biosci 2023; 10:1178382. [PMID: 37795219 PMCID: PMC10546393 DOI: 10.3389/fmolb.2023.1178382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 08/16/2023] [Indexed: 10/06/2023] Open
Abstract
Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with genetic modifications for tumor selectivity, safety, and immunogenicity. Despite these modifications, HSV-1 OV immunotherapies are often treated with the same biosafety guidelines as the wild-type virus, potentially leading to reduced patient access and logistical hurdles for treatment centers, including community treatment centers and small group or private practices, and healthcare workers. Despite the lack of real-world evidence documenting possible transmission to close contacts, and in the setting of shedding and biodistribution analyses for T-VEC demonstrating limited infectivity and low risk of spread to healthcare workers, barriers to treatment with OV immunotherapies remain. With comprehensive information and educational programs, our hope is that updated biosafety guidance on OV immunotherapies will reduce logistical hurdles to ensure that patients have access to these innovative and potentially life-saving medicines across treatment settings. This work reviews a comprehensive collection of data in conjunction with the opinions of the authors based on their clinical experience to provide the suggested framework and key considerations for implementing biosafety protocols for OV immunotherapies, namely T-VEC, the only approved agent to date.
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Affiliation(s)
| | - Nathalie C. Zeitouni
- University of Arizona College of Medicine and US Dermatology Partners, Phoenix, AZ, United States
| | - Marlana Orloff
- Thomas Jefferson University Hospital, Philadelphia, PA, United States
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26
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Slama Y, Ah-Pine F, Khettab M, Arcambal A, Begue M, Dutheil F, Gasque P. The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential. Int J Mol Sci 2023; 24:13511. [PMID: 37686315 PMCID: PMC10488262 DOI: 10.3390/ijms241713511] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.
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Affiliation(s)
- Youssef Slama
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Franck Ah-Pine
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Mohamed Khettab
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Angelique Arcambal
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Mickael Begue
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Fabien Dutheil
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Philippe Gasque
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
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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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28
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Dabo-Trubelja A, Gottumukkala V. Review of cancer therapies for the perioperative physician. Perioper Med (Lond) 2023; 12:25. [PMID: 37312150 PMCID: PMC10262136 DOI: 10.1186/s13741-023-00315-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 05/20/2023] [Indexed: 06/15/2023] Open
Abstract
Advances in cancer treatments over the past decades combining chemotherapy with novel technologies in immunotherapies, radiation therapies, and interventional radiology have prolonged life expectancy. Patients have more options for treatments of their primary or metastatic diseases. Increased procedural techniques amid an aging population with multiple comorbidities present risks and challenges in the perioperative period.Chemotherapy remains the mainstay of cancer treatment, can be given intraoperatively, and is combined with other treatment modalities. Immunotherapy is particular to cancer cells while being less toxic to healthy cells. Cancer vaccines stimulate the immune system to stop disease progression. Oncolytic viruses enhance the immune system's cytotoxic effect and show promise to halt metastatic disease progression if present in the perioperative period. Novel techniques in radiation therapy combined with traditional treatments show enhanced survival. This review focuses on current cancer treatments encountered in the perioperative period.
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Affiliation(s)
- Anahita Dabo-Trubelja
- Department of Anesthesiology and Critical Care, Onco-Anesthesia Fellowship, Perioperative Echocardiography and Ultrasound, Memorial Sloan Kettering Cancer Center of Weill Cornell Medical Center, 1274 York Ave C-330, New York, NY, 10065, USA.
| | - Vijaya Gottumukkala
- Department of Anesthesiology and Perioperative Medicine Program for Advancement of Perioperative Cancer Care, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
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Zolaly MA, Mahallawi W, Khawaji ZY, Alahmadi MA. The Clinical Advances of Oncolytic Viruses in Cancer Immunotherapy. Cureus 2023; 15:e40742. [PMID: 37485097 PMCID: PMC10361339 DOI: 10.7759/cureus.40742] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
A promising future for oncology treatment has been brought about by the emergence of a novel approach utilizing oncolytic viruses in cancer immunotherapy. Oncolytic viruses are viruses that have been exploited genetically to assault malignant cells and activate a robust immune response. Several techniques have been developed to endow viruses with an oncolytic activity through genetic engineering. For instance, redirection capsid modification, stimulation of anti-neoplastic immune response, and genetically arming viruses with cytokines such as IL-12. Oncolytic viral clinical outcomes are sought after, particularly in more advanced cancers. The effectiveness and safety profile of the oncolytic virus in clinical studies with or without the combination of standard treatment (chemotherapy, radiotherapy, or primary excision) has been assessed using response evaluation criteria in solid tumors (RECIST). This review will comprehensively outline the most recent clinical applications and provide the results from various phases of clinical trials in a variety of cancers in the latest published literature.
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Affiliation(s)
- Mohammed A Zolaly
- Pediatric Hematology Oncology, Taibah University, Al-Madinah al-Munawwarah, SAU
| | - Waleed Mahallawi
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Taibah University, Al-Madinah al-Munawwarah, SAU
| | - Zakaria Y Khawaji
- Medicine and Surgery, Taibah University, Al-Madinah al-Munawwarah, SAU
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30
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Gong W, Zhao X, Tang X, Gao L, Sun Y, Ma J. Infectious Recombinant Senecavirus A Expressing p16 INK4A Protein. Int J Mol Sci 2023; 24:ijms24076139. [PMID: 37047110 PMCID: PMC10093924 DOI: 10.3390/ijms24076139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Senecavirus A (SVA) is an oncolytic RNA virus, and it is the ideal oncolytic virus that can be genetically engineered for editing. However, there has not been much exploration into creating SVA viruses that carry antitumor genes to increase their oncolytic potential. The construction of SVA viruses carrying antitumor genes that enhance oncolytic potential has not been fully explored. In this study, a recombinant SVA-CH-01-2015 virus (p15A-SVA-clone) expressing the human p16INK4A protein, also known as cell cycle-dependent protein kinase inhibitor 2A (CDKN2A), was successfully rescued and characterized. The recombinant virus, called SVA-p16, exhibited similar viral replication kinetics to the parent virus, was genetically stable, and demonstrated enhanced antitumor effects in Ishikawa cells. Additionally, another recombinant SVA virus carrying a reporter gene (iLOV), SVA-iLOV, was constructed and identified using the same construction method as an auxiliary validation. Collectively, this study successfully created a new recombinant virus, SVA-p16, that showed increased antitumor effects and could serve as a model for further exploring the antitumor potential of SVA as an oncolytic virus.
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Affiliation(s)
- Wencheng Gong
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Xiaoya Zhao
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Xiaoyu Tang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Long Gao
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Yuan Sun
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Jingyun Ma
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
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31
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Penza V, Maroun JW, Nace RA, Schulze AJ, Russell SJ. Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model. Mol Ther Oncolytics 2023; 28:15-30. [PMID: 36619293 PMCID: PMC9800256 DOI: 10.1016/j.omto.2022.11.006] [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: 09/14/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
Mengovirus is an oncolytic picornavirus whose broad host range allows for testing in immunocompetent cancer models. Two pathogenicity-ablating approaches, polycytidine (polyC) tract truncation and microRNA (miRNA) targets insertion, eliminated the risk of encephalomyocarditis. To investigate whether a polyC truncated, miRNA-detargeted oncolytic Mengovirus might be boosted, we partially or fully rebuilt the polyC tract into the 5' noncoding region (NCR) of polyC-deleted (MC0) oncolytic constructs (NC) carrying miRNA target (miRT) insertions to eliminate cardiac/muscular (miR-133b and miR-208a) and neuronal (miR-124) tropisms. PolyC-reconstituted viruses (MC24-NC and MC37-NC) replicated in vitro and showed the expected tropism restrictions, but reduced cytotoxicity and miRT deletions were frequently observed. In the MPC-11 immune competent mouse plasmacytoma model, both intratumoral and systemic administration of MC0-NC led to faster tumor responses than MC24-NC or MC37-NC, with combined durable complete response rates of 75%, 0.5%, and 30%, respectively. Secondary viremia was higher following MC0-NC versus MC24-NC or MC37-NC therapy. Sequence analysis of virus progeny from treated mice revealed a high prevalence of miRT sequences loss among MC24- and MC37- viral genomes, but not in MC0-NC. Overall, MC0-NC was capable of stably retaining miRT sites and provided a more effective treatment and is therefore our lead Mengovirus candidate for clinical translation.
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Affiliation(s)
- Velia Penza
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55902, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA
| | - Justin W. Maroun
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN 55902, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA
| | - Rebecca A. Nace
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA
| | - Autumn J. Schulze
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA
| | - Stephen J. Russell
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN 55902, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
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32
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Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication. Mol Ther Methods Clin Dev 2022; 28:190-207. [PMID: 36700123 PMCID: PMC9843450 DOI: 10.1016/j.omtm.2022.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022]
Abstract
Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.
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33
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Hu H, Xia Q, Hu J, Wang S. Oncolytic Viruses for the Treatment of Bladder Cancer: Advances, Challenges, and Prospects. J Clin Med 2022; 11:jcm11236997. [PMID: 36498574 PMCID: PMC9738443 DOI: 10.3390/jcm11236997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/16/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Bladder cancer is one of the most prevalent cancers. Despite recent advancements in bladder cancer therapy, new strategies are still required for improving patient outcomes, particularly for those who experienced Bacille Calmette-Guerin failure and those with locally advanced or metastatic bladder cancer. Oncolytic viruses are either naturally occurring or purposefully engineered viruses that have the ability to selectively infect and lyse tumor cells while avoiding harming healthy cells. In light of this, oncolytic viruses serve as a novel and promising immunotherapeutic strategy for bladder cancer. A wide diversity of viruses, including adenoviruses, herpes simplex virus, coxsackievirus, Newcastle disease virus, vesicular stomatitis virus, alphavirus, and vaccinia virus, have been studied in many preclinical and clinical studies for their potential as oncolytic agents for bladder cancer. This review aims to provide an overview of the advances in oncolytic viruses for the treatment of bladder cancer and highlights the challenges and research directions for the future.
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Affiliation(s)
| | | | - Jia Hu
- Correspondence: (J.H.); (S.W.)
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34
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Recent advances in microbial toxin-related strategies to combat cancer. Semin Cancer Biol 2022; 86:753-768. [PMID: 34271147 DOI: 10.1016/j.semcancer.2021.07.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/01/2021] [Accepted: 07/09/2021] [Indexed: 02/08/2023]
Abstract
It is a major concern to treat cancer successfully, due to the distinctive pathophysiology of cancer cells and the gradual manifestation of resistance. Specific action, adverse effects and development of resistance has prompted the urgent requirement of exploring alternative anti-tumour treatment therapies. The naturally derived microbial toxins as a therapy against cancer cells are a promisingly new dimension. Various important microbial toxins such as Diphtheria toxin, Vibrio cholera toxin, Aflatoxin, Patulin, Cryptophycin-55, Chlorella are derived from several bacterial, fungal and algal species. These agents act on different biotargets such as inhibition of protein synthesis, reduction in cell growth, regulation of cell cycle and many cellular processes. Bacterial toxins produce actions primarily by targeting protein moieties and some immunomodulation and few acts through DNA. Fungal toxins appear to have more DNA damaging activity and affect the cell cycle. Algal toxins produce alteration in mitochondrial phosphorylation. In conclusion, microbial toxins and their metabolites appear to have a great potential to provide a promising option for the treatment and management to combat cancer.
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35
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Ma XY, Hill BD, Hoang T, Wen F. Virus-inspired strategies for cancer therapy. Semin Cancer Biol 2022; 86:1143-1157. [PMID: 34182141 PMCID: PMC8710185 DOI: 10.1016/j.semcancer.2021.06.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/17/2021] [Accepted: 06/23/2021] [Indexed: 01/27/2023]
Abstract
The intentional use of viruses for cancer therapy dates back over a century. As viruses are inherently immunogenic and naturally optimized delivery vehicles, repurposing viruses for drug delivery, tumor antigen presentation, or selective replication in cancer cells represents a simple and elegant approach to cancer treatment. While early virotherapy was fraught with harsh side effects and low response rates, virus-based therapies have recently seen a resurgence due to newfound abilities to engineer and tune oncolytic viruses, virus-like particles, and virus-mimicking nanoparticles for improved safety and efficacy. However, despite their great potential, very few virus-based therapies have made it through clinical trials. In this review, we present an overview of virus-inspired approaches for cancer therapy, discuss engineering strategies to enhance their mechanisms of action, and highlight their application for overcoming the challenges of traditional cancer therapies.
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Affiliation(s)
- Xiao Yin Ma
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Brett D Hill
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Trang Hoang
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Fei Wen
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States.
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36
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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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37
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Zhang Y, Nagalo BM. Immunovirotherapy Based on Recombinant Vesicular Stomatitis Virus: Where Are We? Front Immunol 2022; 13:898631. [PMID: 35837384 PMCID: PMC9273848 DOI: 10.3389/fimmu.2022.898631] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/31/2022] [Indexed: 01/05/2023] Open
Abstract
Vesicular stomatitis virus (VSV), a negative-strand RNA virus of the Vesiculovirus genus, has demonstrated encouraging anti-neoplastic activity across multiple human cancer types. VSV is particularly attractive as an oncolytic agent because of its broad tropism, fast replication kinetics, and amenability to genetic manipulations. Furthermore, VSV-induced oncolysis can elicit a potent antitumor cytotoxic T-cell response to viral proteins and tumor-associated antigens, resulting in a long-lasting antitumor effect. Because of this multifaceted immunomodulatory property, VSV was investigated extensively as an immunovirotherapy alone or combined with other anticancer modalities, such as immune checkpoint blockade. Despite these recent opportunities to delineate synergistic and additive antitumor effects with existing anticancer therapies, FDA approval for the use of oncolytic VSV in humans has not yet been granted. This mini-review discusses factors that have prompted the use of VSV as an immunovirotherapy in human cancers and provides insights into future perspectives and research areas to improve VSV-based oncotherapy.
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Affiliation(s)
- Yuguo Zhang
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Bolni Marius Nagalo
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- *Correspondence: Bolni Marius Nagalo,
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38
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Nadukkandy AS, Ganjoo E, Singh A, Dinesh Kumar L. Tracing New Landscapes in the Arena of Nanoparticle-Based Cancer Immunotherapy. FRONTIERS IN NANOTECHNOLOGY 2022. [DOI: 10.3389/fnano.2022.911063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Over the past two decades, unique and comprehensive cancer treatment has ushered new hope in the holistic management of the disease. Cancer immunotherapy, which harnesses the immune system of the patient to attack the cancer cells in a targeted manner, scores over others by being less debilitating compared to the existing treatment strategies. Significant advancements in the knowledge of immune surveillance in the last few decades have led to the development of several types of immune therapy like monoclonal antibodies, cancer vaccines, immune checkpoint inhibitors, T-cell transfer therapy or adoptive cell therapy (ACT) and immune system modulators. Intensive research has established cancer immunotherapy to be a safe and effective method for improving survival and the quality of a patient’s life. However, numerous issues with respect to site-specific delivery, resistance to immunotherapy, and escape of cancer cells from immune responses, need to be addressed for expanding and utilizing this therapy as a regular mode in the clinical treatment. Development in the field of nanotechnology has augmented the therapeutic efficiency of treatment modalities of immunotherapy. Nanocarriers could be used as vehicles because of their advantages such as increased surface areas, targeted delivery, controlled surface and release chemistry, enhanced permeation and retention effect, etc. They could enhance the function of immune cells by incorporating immunomodulatory agents that influence the tumor microenvironment, thus enabling antitumor immunity. Robust validation of the combined effect of nanotechnology and immunotherapy techniques in the clinics has paved the way for a better treatment option for cancer than the already existing procedures such as chemotherapy and radiotherapy. In this review, we discuss the current applications of nanoparticles in the development of ‘smart’ cancer immunotherapeutic agents like ACT, cancer vaccines, monoclonal antibodies, their site-specific delivery, and modulation of other endogenous immune cells. We also highlight the immense possibilities of using nanotechnology to accomplish leveraging the coordinated and adaptive immune system of a patient to tackle the complexity of treating unique disease conditions and provide future prospects in the field of cancer immunotherapy.
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Clinical activity of single-dose systemic oncolytic VSV virotherapy in patients with relapsed refractory T-cell lymphoma. Blood Adv 2022; 6:3268-3279. [PMID: 35175355 PMCID: PMC9198941 DOI: 10.1182/bloodadvances.2021006631] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/25/2022] [Indexed: 12/14/2022] Open
Abstract
Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-β (IFN-β) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNβ-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 × 1011 TCID50), and 6 were treated at DL4 (1.7 × 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-β, a biomarker of VSV-IFNβ-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-β of 18 213 pg/mL, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL, resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. This trial is registered at www.clinicaltrials.gov as #NCT03017820.
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40
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Wang S, Wei J. Distinguishing the Pros and Cons of Metabolic Reprogramming in Oncolytic Virus Immunotherapy. Int J Cancer 2022; 151:1654-1662. [PMID: 35633046 DOI: 10.1002/ijc.34139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/11/2022] [Accepted: 05/16/2022] [Indexed: 11/12/2022]
Abstract
Oncolytic viruses (OVs) represent a class of cancer immunotherapies that rely on hijacking the host cell factory for replicative oncolysis and eliciting immune responses for tumor clearance. An increasing evidence suggests that the metabolic state of tumor cells and immune cells is a putative determinant of the efficacy of cancer immunotherapy. However, how therapeutic intervention with OVs affects metabolic fluxes within the tumor microenvironment (TME) remains poorly understood. Herein, we review the complexities of metabolic reprogramming involving the effects of viruses and their consequences on tumor cells and immune cells. We highlight the inherent drawback of oncolytic virotherapy, namely that treatment with OVs inevitably further exacerbates the depletion of nutrients and the accumulation of metabolic wastes in the TME, leading to a metabolic barrier to antitumor immune responses. We also describe targeted metabolic strategies that can be used to unlock the therapeutic potential of OVs.
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Affiliation(s)
- Shiqun Wang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, P.R. China
| | - Jiwu Wei
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, P.R. China
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41
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Keshavarz M, Mohammad Miri S, Behboudi E, Arjeini Y, Dianat-Moghadam H, Ghaemi A. Oncolytic virus delivery modulated immune responses toward cancer therapy: Challenges and perspectives. Int Immunopharmacol 2022; 108:108882. [PMID: 35623296 DOI: 10.1016/j.intimp.2022.108882] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 11/05/2022]
Abstract
Oncolytic viruses (OVs) harness the hallmarks of tumor cells and cancer-related immune responses for the lysis of malignant cells, modulation of the tumor microenvironment, and exertion of vaccine-like activities. However, efficient clinical exploitation of these potent therapeutic modules requires their systematic administration, especially against metastatic and solid tumors. Therefore, developing methods for shielding a virus from the neutralizing environment of the bloodstream while departing toward tumor sites is a must. This paper reports the latest advancements in the employment of chemical and biological compounds aimed at safe and efficient delivery of OVs to target tissues or tumor deposits within the host.
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Affiliation(s)
- Mohsen Keshavarz
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Seyed Mohammad Miri
- Department of Influenza and Other Respiratory Viruses, Pasteur Institute of Iran, Tehran, Iran.
| | - Emad Behboudi
- Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Yaser Arjeini
- Department of Research and Development, Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran.
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amir Ghaemi
- Department of Influenza and Other Respiratory Viruses, Pasteur Institute of Iran, Tehran, Iran.
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Intravenous Oncolytic Vaccinia Virus Therapy Results in a Differential Immune Response between Cancer Patients. Cancers (Basel) 2022; 14:cancers14092181. [PMID: 35565310 PMCID: PMC9103071 DOI: 10.3390/cancers14092181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Oncolytic viruses (OVs) have been extensively studied as an immunotherapeutic agent against a variety of cancers with some successes. Immunotherapeutic strategies, such as OVs, aim to transform an immunologically ‘cold’ tumour microenvironment into a more favourable inflammatory ‘hot’ tumour. However, it is evident that not all patients have a favourable response to treatment. Furthermore, reliable biomarkers able to predict a patient’s response to therapy have not yet been elucidated. We show evidence of a distinct immunologically exhausted profile in patients who do not respond to OV, which may pave the way for the development of predictive biomarkers leading to a more personalised approach to cancer treatment using combination therapies. Abstract Pexa-Vec is an engineered Wyeth-strain vaccinia oncolytic virus (OV), which has been tested extensively in clinical trials, demonstrating enhanced cytotoxic T cell infiltration into tumours following treatment. Favourable immune consequences to Pexa-Vec include the induction of an interferon (IFN) response, followed by inflammatory cytokine/chemokine secretion. This promotes tumour immune infiltration, innate and adaptive immune cell activation and T cell priming, culminating in targeted tumour cell killing, i.e., an immunologically ‘cold’ tumour microenvironment is transformed into a ‘hot’ tumour. However, as with all immunotherapies, not all patients respond in a uniformly favourable manner. Our study herein, shows a differential immune response by patients to intravenous Pexa-Vec therapy, whereby some patients responded to the virus in a typical and expected manner, demonstrating a significant IFN induction and subsequent peripheral immune activation. However, other patients experienced a markedly subdued immune response and appeared to exhibit an exhausted phenotype at baseline, characterised by higher baseline immune checkpoint expression and regulatory T cell (Treg) levels. This differential baseline immunological profile accurately predicted the subsequent response to Pexa-Vec and may, therefore, enable the development of predictive biomarkers for Pexa-Vec and OV therapies more widely. If confirmed in larger clinical trials, these immunological biomarkers may enable a personalised approach, whereby patients with an exhausted baseline immune profile are treated with immune checkpoint blockade, with the aim of reversing immune exhaustion, prior to or alongside OV therapy.
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Identification of the receptor of oncolytic virus M1 as a therapeutic predictor for multiple solid tumors. Signal Transduct Target Ther 2022; 7:100. [PMID: 35393389 PMCID: PMC8989880 DOI: 10.1038/s41392-022-00921-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/29/2022] [Accepted: 02/10/2022] [Indexed: 11/08/2022] Open
Abstract
Over the last decade, oncolytic virus (OV) therapy has shown its promising potential in tumor treatment. The fact that not every patient can benefit from it highlights the importance for defining biomarkers that help predict patients' responses. As particular self-amplifying biotherapeutics, the anti-tumor effects of OVs are highly dependent on the host factors for viral infection and replication. By using weighted gene co-expression network analysis (WGCNA), we found matrix remodeling associated 8 (MXRA8) is positively correlated with the oncolysis induced by oncolytic virus M1 (OVM). Consistently, MXRA8 promotes the oncolytic efficacy of OVM in vitro and in vivo. Moreover, the interaction of MXRA8 and OVM studied by single-particle cryo-electron microscopy (cryo-EM) showed that MXRA8 directly binds to this virus. Therefore, MXRA8 acts as the entry receptor of OVM. Pan-cancer analysis showed that MXRA8 is abundant in most solid tumors and is highly expressed in tumor tissues compared with adjacent normal ones. Further study in cancer cell lines and patient-derived tumor tissues revealed that the tumor selectivity of OVM is predominantly determined by a combinational effect of the cell membrane receptor MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP). Taken together, our study may provide a novel dual-biomarker for precision medicine in OVM therapy.
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44
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Tian Y, Xie D, Yang L. Engineering strategies to enhance oncolytic viruses in cancer immunotherapy. Signal Transduct Target Ther 2022; 7:117. [PMID: 35387984 PMCID: PMC8987060 DOI: 10.1038/s41392-022-00951-x] [Citation(s) in RCA: 123] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023] Open
Abstract
Oncolytic viruses (OVs) are emerging as potentially useful platforms in treatment methods for patients with tumors. They preferentially target and kill tumor cells, leaving healthy cells unharmed. In addition to direct oncolysis, the essential and attractive aspect of oncolytic virotherapy is based on the intrinsic induction of both innate and adaptive immune responses. To further augment this efficacious response, OVs have been genetically engineered to express immune regulators that enhance or restore antitumor immunity. Recently, combinations of OVs with other immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptors (CARs), antigen-specific T-cell receptors (TCRs) and autologous tumor-infiltrating lymphocytes (TILs), have led to promising progress in cancer treatment. This review summarizes the intrinsic mechanisms of OVs, describes the optimization strategies for using armed OVs to enhance the effects of antitumor immunity and highlights rational combinations of OVs with other immunotherapies in recent preclinical and clinical studies.
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Affiliation(s)
- Yaomei Tian
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China
- College of Bioengineering, Sichuan University of Science & Engineering, No. 519, Huixing Road, 643000, Zigong, Sichuan, People's Republic of China
| | - Daoyuan Xie
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China
| | - Li Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China.
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45
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The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors. NANOMATERIALS 2021; 11:nano11113018. [PMID: 34835785 PMCID: PMC8623458 DOI: 10.3390/nano11113018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023]
Abstract
While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.
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Sun H, Li J, Hu W, Yan Y, Guo Z, Zhang Z, Chen Y, Yao X, Teng L, Wang X, Li L, Chai D, Zheng J, Wang G. Co-immunizing with HMGB1 enhances anti-tumor immunity of B7H3 vaccine in renal carcinoma. Mol Immunol 2021; 139:184-192. [PMID: 34560414 DOI: 10.1016/j.molimm.2021.09.002] [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: 05/07/2021] [Revised: 08/16/2021] [Accepted: 09/02/2021] [Indexed: 11/27/2022]
Abstract
Metastatic renal carcinoma is a kind of tumor with high degree of malignancy, but there are no effective treatment methods and strategies at present. In this study, we designed a folate-grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of high mobility group box 1 protein (HMGB1) and a tumor-specific antigen of B7H3 (CD276) for renal carcinoma therapy. Mice bearing subcutaneous human B7H3 (hB7H3)-Renca tumor were immunized with H1-pHMGB1/pB7H3, H1-pB7H3, H1-pHMGB1, or Mock vaccine. Compared to other control groups, the growth of the tumor was significantly inhibited in H1-pHMGB1/pB7H3 vaccine group. The increased proportion and mature of CD11c+ DCs were observed in the spleen of H1-pHMGB1/pB7H3 treated mice. Likewise, HMGB1 promoted B7H3 vaccine to induce tumor-specific CD8+ T cell proliferation and CTL responses. Beyond that, H1-pHMGB1/pB7H3 vaccine strengthened the induction of functional CD8+ T cells. With the depletion of CD8+ T cells, the anti-tumor effect of H1-pHMGB1/pB7H3 also disappeared, indicating that CD8+ T cells are the key factor of the anti-tumor activity of the vaccine. So, to sum up, H1-pHMGB1/pB7H3 vaccine could achieve the desired anti-tumor effect by enhancing the response of tumor-specific functional CD8+ T cell responses. H1 nanoparticle-based vaccines may have great potential and prospect in the treatment of primary solid tumors.
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Affiliation(s)
- Huanyou Sun
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Juan Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Wenwen Hu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Yinan Yan
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Zengli Guo
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Zichun Zhang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Yuxin Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Xuefan Yao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Ling Teng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Xinyuan Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Liantao Li
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Dafei Chai
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
| | - Junnian Zheng
- Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
| | - Gang Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
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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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Appolloni I, Alessandrini F, Menotti L, Avitabile E, Marubbi D, Piga N, Ceresa D, Piaggio F, Campadelli-Fiume G, Malatesta P. Specificity, Safety, Efficacy of EGFRvIII-Retargeted Oncolytic HSV for Xenotransplanted Human Glioblastoma. Viruses 2021; 13:1677. [PMID: 34578259 PMCID: PMC8473268 DOI: 10.3390/v13091677] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/04/2021] [Accepted: 08/16/2021] [Indexed: 11/27/2022] Open
Abstract
Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across the tumor cells represent an intriguing treatment strategy. Here, we tested the specificity, safety and efficacy of R-613, the first oncolytic HSV fully retargeted to EGFRvIII, a variant of the epidermal growth factor receptor carrying a mutation typically found in glioblastoma. An early treatment with R-613 on orthotopically transplanted EGFRvIII-expressing human glioblastoma significantly increased the median survival time of mice. In this setting, the growth of human glioblastoma xenotransplants was monitored by a secreted luciferase reporter and showed that R-613 is able to substantially delay the development of the tumor masses. When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment.
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Affiliation(s)
- Irene Appolloni
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (I.A.); (D.M.); (N.P.); (F.P.)
| | | | - Laura Menotti
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; (L.M.); (E.A.)
| | - Elisa Avitabile
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; (L.M.); (E.A.)
| | - Daniela Marubbi
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (I.A.); (D.M.); (N.P.); (F.P.)
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.A.); (D.C.)
| | - Noemi Piga
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (I.A.); (D.M.); (N.P.); (F.P.)
| | - Davide Ceresa
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.A.); (D.C.)
| | - Francesca Piaggio
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (I.A.); (D.M.); (N.P.); (F.P.)
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.A.); (D.C.)
| | - Gabriella Campadelli-Fiume
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy;
| | - Paolo Malatesta
- Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy; (I.A.); (D.M.); (N.P.); (F.P.)
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.A.); (D.C.)
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Penza V, Russell SJ, Schulze AJ. The long-lasting enigma of polycytidine (polyC) tract. PLoS Pathog 2021; 17:e1009739. [PMID: 34347852 PMCID: PMC8336851 DOI: 10.1371/journal.ppat.1009739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Long polycytidine (polyC) tracts varying in length from 50 to 400 nucleotides were first described in the 5'-noncoding region (NCR) of genomes of picornaviruses belonging to the Cardio- and Aphthovirus genera over 50 years ago, but the molecular basis of their function is still unknown. Truncation or complete deletion of the polyC tracts in picornaviruses compromises virulence and pathogenicity but do not affect replicative fitness in vitro, suggesting a role as "viral security" RNA element. The evidence available suggests that the presence of a long polyC tract is required for replication in immune cells, which impacts viral distribution and targeting, and, consequently, pathogenic progression. Viral attenuation achieved by reduction of the polyC tract length has been successfully used for vaccine strategies. Further elucidation of the role of the polyC tract in viral replication cycle and its connection with replication in immune cells has the potential to expand the arsenal of tools in the fight against cancer in oncolytic virotherapy (OV). Here, we review the published data on the biological significance and mechanisms of action of the polyC tract in viral pathogenesis in Cardio- and Aphthoviruses.
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Affiliation(s)
- Velia Penza
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Stephen J. Russell
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Autumn J. Schulze
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
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50
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Núñez-Manchón E, Farrera-Sal M, Otero-Mateo M, Castellano G, Moreno R, Medel D, Alemany R, Villanueva E, Fillat C. Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses. NAR Cancer 2021; 3:zcab015. [PMID: 34316705 PMCID: PMC8210037 DOI: 10.1093/narcan/zcab015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 02/26/2021] [Accepted: 04/21/2021] [Indexed: 11/14/2022] Open
Abstract
Arming oncolytic adenoviruses with therapeutic transgenes is a well-established strategy for multimodal tumour attack. However, this strategy sometimes leads to unexpected attenuated viral replication and a loss of oncolytic effects, preventing these viruses from reaching the clinic. Previous work has shown that altering codon usage in viral genes can hamper viral fitness. Here, we have analysed how transgene codon usage impacts viral replication and oncolytic activity. We observe that, although transgenes with optimized codons show high expression levels at the first round of infection, they impair viral fitness and are therefore not expressed in a sustained manner. Conversely, transgenes encoded by suboptimal codons do not compromise viral replication and are thus stably expressed over time, allowing a greater oncolytic activity both in vitro and in vivo. Altogether, our work shows that fine-tuning codon usage leads to a concerted optimization of transgene expression and viral replication paving the way for the rational design of more efficacious oncolytic therapies.
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Affiliation(s)
- Estela Núñez-Manchón
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036-Barcelona, Spain
| | - Martí Farrera-Sal
- Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, 08907-L'Hospitalet de Llobregat, Spain
| | - Marc Otero-Mateo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036-Barcelona, Spain
| | - Giancarlo Castellano
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036-Barcelona, Spain
| | - Rafael Moreno
- Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, 08907-L'Hospitalet de Llobregat, Spain
| | - David Medel
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036-Barcelona, Spain
| | - Ramon Alemany
- Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, 08907-L'Hospitalet de Llobregat, Spain
| | - Eneko Villanueva
- Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK
| | - Cristina Fillat
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036-Barcelona, Spain
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