|
1
|
Huberts M, de Graaf JF, Groeneveld D, van Nieuwkoop S, Fouchier RA, van den Hoogen BG. Cell-derived Newcastle disease virus variant with two amino acid substitutions near cleavage site of F shows favorable traits as oncolytic virus. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200915. [PMID: 39802675 PMCID: PMC11719830 DOI: 10.1016/j.omton.2024.200915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/21/2024] [Accepted: 12/03/2024] [Indexed: 01/16/2025]
Abstract
Newcastle disease virus (NDV) has shown encouraging effectiveness in in vitro, in vivo, and in early clinical trials as a viro-immunotherapy for pancreatic cancer. Previously, NDV used in clinical trials was produced in embryonated chicken eggs; however, egg-produced viruses are known to be partly neutralized by the human complement system when administered intravenously. Here, an NDV variant (NDV F0) was generated for production in mammalian cells, without passage in eggs. This was achieved by introducing the V-106-M and L-117-S amino acid substitutions upstream of the cleavage site in the F protein, resulting in rNDV F0-M, rNDV F0-S, and NDV F0-M/S. These viruses can be considered non-virulent as determined with in vivo pathogenicity testing and were neutralized less by the human complement system, which is explained by CD46 expression on the viral membrane. The inoculation of 10 pancreatic cancer cell lines demonstrated similar or enhanced replication and cell-killing efficacy of rNDV F0-M/S compared to rNDV F0 and rNDV F0-M. In conclusion, NDV F0 variants with M and S substitutions are non-virulent, effective oncolytic viruses that can be produced in mammalian cells, potentially resulting in a more effective treatment option for pancreatic cancer patients compared to rNDV F0.
Collapse
Affiliation(s)
- Marco Huberts
- Department of Viroscience, Erasmus Medical Centrum, Doctor Molewaterplein 40, 3015 CN Rotterdam, the Netherlands
| | - J. Fréderique de Graaf
- Department of Immunology, Leids Universitair Medisch Centrum, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Daphne Groeneveld
- Department of Viroscience, Erasmus Medical Centrum, Doctor Molewaterplein 40, 3015 CN Rotterdam, the Netherlands
| | - Stefan van Nieuwkoop
- Department of Viroscience, Erasmus Medical Centrum, Doctor Molewaterplein 40, 3015 CN Rotterdam, the Netherlands
| | - Ron A.M. Fouchier
- Department of Viroscience, Erasmus Medical Centrum, Doctor Molewaterplein 40, 3015 CN Rotterdam, the Netherlands
| | - Bernadette G. van den Hoogen
- Department of Viroscience, Erasmus Medical Centrum, Doctor Molewaterplein 40, 3015 CN Rotterdam, the Netherlands
| |
Collapse
|
|
2
|
Cheow PS, Tan TK, Song AAL, Yusoff K, Chia SL. Development of a recombinant non-replicating Newcastle disease virus. Avian Pathol 2025; 54:149-157. [PMID: 39318350 DOI: 10.1080/03079457.2024.2403412] [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: 09/26/2023] [Revised: 08/02/2024] [Accepted: 09/03/2024] [Indexed: 09/26/2024]
Abstract
RESEARCH HIGHLIGHTS Development of nr-NDV.Reverse transfection was applied for the recovery of nr-NDV.Propagation of nr-NDV was done by sub-passaging transfected BSR T7/5 cells.Safety profile was done to prove that the nr-NDV is non-replicating.
Collapse
Affiliation(s)
| | - Tiong Kit Tan
- MRC Translate Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Adelene Ai-Lian Song
- Department of Microbiology, Faculty of Biotechnology & Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | | | - Suet Lin Chia
- Malaysia Genome and Vaccine Institute, Kajang, Malaysia
- Department of Microbiology, Faculty of Biotechnology & Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
| |
Collapse
|
|
3
|
Lundstrom K. Viral Vector-Based Cancer Vaccines. Methods Mol Biol 2025; 2926:101-127. [PMID: 40266521 DOI: 10.1007/978-1-0716-4542-0_9] [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] [Indexed: 04/24/2025]
Abstract
Viral vectors have been frequently used as vaccine-delivery vehicles. Both DNA and RNA viruses have been employed for vaccine development. Viral vectors based on adenoviruses (Ad), adeno-associated viruses (AAV), herpes simplex viruses (HSV), lentiviruses (LV), alphaviruses, flaviviruses, measles viruses (MV), rhabdoviruses, Newcastle disease virus (NDV), poxviruses and picornaviruses have been utilized. Approaches have included the expression of tumor-associated antigens and immunostimulatory genes as well as administration of oncolytic viruses. Prophylactic and therapeutic proof-of-concept has been established in preclinical animal tumor models, and therapeutic efficacy has been obtained in clinical trials in human cancer patients. Model viral vector systems and their applications in cancer vaccine development are described here.
Collapse
|
|
4
|
Rosewell Shaw A, Morita D, Porter CE, Tu E, Biegert GW, Agrawal S, Durham N, Brenner MK, Suzuki M. IL-12 encoding oNDV synergizes with CAR-T cells in orthotopic models of non-small cell lung cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200899. [PMID: 39624055 PMCID: PMC11609364 DOI: 10.1016/j.omton.2024.200899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 09/24/2024] [Accepted: 10/24/2024] [Indexed: 02/28/2025]
Abstract
Systemic administration of oncolytic viruses (OVs) is a promising approach for targeting metastatic solid tumors, but their anti-tumor activity is limited by pre-existing neutralizing antibodies against common human viruses. Therefore, investigators have developed OVs derived from non-human host viruses. Successful implementation of this strategy requires that the viral vector selectively infects and replicates within human cancer cells. Newcastle disease virus (NDV) is an avian paramyxovirus that, as NDV-based OVs (oNDVs), has demonstrated safety and activity against multiple human tumors in clinical trials. Their use as a single agent, however, is insufficient to cure tumors. Similarly, chimeric antigen receptor-modified T cells (CAR-T cells) enable systemic targeting of cancer cells but have limited anti-tumor effects against bulky solid tumors, in part due to the immunosuppressive tumor environment. In this study, we evaluated the anti-tumor effects of combining systemic oNDV and CAR-T cell treatments. In models of non-small cell lung carcinoma (NSCLC), we found that oNDV itself and interleukin (IL)-12 derived from oNDVs enhance HER2-directed CAR-T cell anti-tumor activity and persistence in vitro and in vivo, leading to superior control of NSCLC tumors compared with either agent alone in vivo. Our data indicate that oNDV enhances the anti-tumor effects of HER2.CAR-T cells, thus controlling the growth of orthotopic NSCLC tumors.
Collapse
Affiliation(s)
- Amanda Rosewell Shaw
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston Methodist Hospital, Houston, TX, USA
- Department of Biology, School of Science and Engineering, Benedict College, Columbia, SC, USA
| | - Daisuke Morita
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston Methodist Hospital, Houston, TX, USA
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
- Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
| | - Caroline E. Porter
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston Methodist Hospital, Houston, TX, USA
| | - Eric Tu
- AstraZeneca, Gaithersburg, MD, USA
| | - Greyson W. Biegert
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston Methodist Hospital, Houston, TX, USA
| | | | | | - Malcolm K. Brenner
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston Methodist Hospital, Houston, TX, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Masataka Suzuki
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston Methodist Hospital, Houston, TX, USA
| |
Collapse
|
|
5
|
Davar D, Carneiro BA, Dy GK, Sheth S, Borad MJ, Harrington KJ, Patel SP, Galanis E, Samson A, Agrawal S, Chen Z, Fan C, Gong M, Burton J, Tu E, Durham N, Laubscher K, Arnaldez F, Zamarin D. Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV-GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors. J Immunother Cancer 2024; 12:e009336. [PMID: 39551600 PMCID: PMC11574399 DOI: 10.1136/jitc-2024-009336] [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: 03/25/2024] [Accepted: 10/13/2024] [Indexed: 11/19/2024] Open
Abstract
BACKGROUND MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors. METHODS This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15-18 days. The dose-escalation phase assessed four-dose levels (108, 109, 1010, 1011 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395. RESULTS 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3-4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 1011 and 1010 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively. CONCLUSION This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER NCT03889275.
Collapse
Affiliation(s)
- Diwakar Davar
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Benedito A Carneiro
- Lifespan Cancer Institute, Legorreta Cancer Institute at Brown University, Providence, Rhode Island, USA
| | - Grace K Dy
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Siddharth Sheth
- Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | - Kevin J Harrington
- Division of Radiotherapy and Imaging, The Institute of Cancer Research / The Royal Marsden NIHR Biomedical Research Centre, London, UK
| | - Sandip P Patel
- University of California San Diego, La Jolla, California, USA
| | | | - Adel Samson
- Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UK
| | - Sonia Agrawal
- Oncology Data Science, Research and Early Development, Oncology R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Zhongying Chen
- Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (CPSS), BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Chunling Fan
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences (CPSS), BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Maozhen Gong
- AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Jenny Burton
- Oncology R&D, AstraZeneca PLC, Cambridge, Cambridgeshire, UK
| | - Eric Tu
- Translational Medicine, Cell Therapy and Oncolytic Viruses, BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Nicholas Durham
- Translational Medicine, Cell Therapy and Oncolytic Viruses, BioPharmaceuticals R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Kevin Laubscher
- Oncology Data Science, Research and Early Development, Oncology R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Fernanda Arnaldez
- Clinical Development, Oncology R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA
| | - Dmitriy Zamarin
- Early Drug Development, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| |
Collapse
|
|
6
|
Meléndez-Vázquez NM, Gomez-Manzano C, Godoy-Vitorino F. Oncolytic Virotherapies and Adjuvant Gut Microbiome Therapeutics to Enhance Efficacy Against Malignant Gliomas. Viruses 2024; 16:1775. [PMID: 39599889 PMCID: PMC11599061 DOI: 10.3390/v16111775] [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: 10/11/2024] [Revised: 11/08/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024] Open
Abstract
Glioblastoma (GBM) is the most prevalent malignant brain tumor. Current standard-of-care treatments offer limited benefits for patient survival. Virotherapy is emerging as a novel strategy to use oncolytic viruses (OVs) for the treatment of GBM. These engineered and non-engineered viruses infect and lyse cancer cells, causing tumor destruction without harming healthy cells. Recent advances in genetic modifications to OVs have helped improve their targeting capabilities and introduce therapeutic genes, broadening the therapeutic window and minimizing potential side effects. The efficacy of oncolytic virotherapy can be enhanced by combining it with other treatments such as immunotherapy, chemotherapy, or radiation. Recent studies suggest that manipulating the gut microbiome to enhance immune responses helps improve the therapeutic efficacy of the OVs. This narrative review intends to explore OVs and their role against solid tumors, especially GBM while emphasizing the latest technologies used to enhance and improve its therapeutic and clinical responses.
Collapse
Affiliation(s)
- Natalie M. Meléndez-Vázquez
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00918, USA;
| | - Candelaria Gomez-Manzano
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Filipa Godoy-Vitorino
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00918, USA;
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Yang H, Tian J, Zhao J, Zhao Y, Zhang G. The Application of Newcastle Disease Virus (NDV): Vaccine Vectors and Tumor Therapy. Viruses 2024; 16:886. [PMID: 38932177 PMCID: PMC11209082 DOI: 10.3390/v16060886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Newcastle disease virus (NDV) is an avian pathogen with an unsegmented negative-strand RNA genome that belongs to the Paramyxoviridae family. While primarily pathogenic in birds, NDV presents no threat to human health, rendering it a safe candidate for various biomedical applications. Extensive research has highlighted the potential of NDV as a vector for vaccine development and gene therapy, owing to its transcriptional modularity, low recombination rate, and lack of a DNA phase during replication. Furthermore, NDV exhibits oncolytic capabilities, efficiently eliciting antitumor immune responses, thereby positioning it as a promising therapeutic agent for cancer treatment. This article comprehensively reviews the biological characteristics of NDV, elucidates the molecular mechanisms underlying its oncolytic properties, and discusses its applications in the fields of vaccine vector development and tumor therapy.
Collapse
Affiliation(s)
- Huiming Yang
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (H.Y.); (J.T.); (J.Z.); (Y.Z.)
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jiaxin Tian
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (H.Y.); (J.T.); (J.Z.); (Y.Z.)
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jing Zhao
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (H.Y.); (J.T.); (J.Z.); (Y.Z.)
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Ye Zhao
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (H.Y.); (J.T.); (J.Z.); (Y.Z.)
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Guozhong Zhang
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (H.Y.); (J.T.); (J.Z.); (Y.Z.)
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| |
Collapse
|
|
9
|
Warner BM, Yates JGE, Vendramelli R, Truong T, Meilleur C, Chan L, Leacy A, Pham PH, Pei Y, Susta L, Wootton SK, Kobasa D. Intranasal vaccination with an NDV-vectored SARS-CoV-2 vaccine protects against Delta and Omicron challenges. NPJ Vaccines 2024; 9:90. [PMID: 38782986 PMCID: PMC11116387 DOI: 10.1038/s41541-024-00870-8] [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: 04/14/2023] [Accepted: 03/29/2024] [Indexed: 05/25/2024] Open
Abstract
The rapid development and deployment of vaccines following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been estimated to have saved millions of lives. Despite their immense success, there remains a need for next-generation vaccination approaches for SARS-CoV-2 and future emerging coronaviruses and other respiratory viruses. Here we utilized a Newcastle Disease virus (NDV) vectored vaccine expressing the ancestral SARS-CoV-2 spike protein in a pre-fusion stabilized chimeric conformation (NDV-PFS). When delivered intranasally, NDV-PFS protected both Syrian hamsters and K18 mice against Delta and Omicron SARS-CoV-2 variants of concern. Additionally, intranasal vaccination induced robust, durable protection that was extended to 6 months post-vaccination. Overall, our data provide evidence that NDV-vectored vaccines represent a viable next-generation mucosal vaccination approach.
Collapse
Affiliation(s)
- Bryce M Warner
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
| | - Jacob G E Yates
- Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada
| | - Robert Vendramelli
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
| | - Thang Truong
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
| | - Courtney Meilleur
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
| | - Lily Chan
- Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada
| | - Alexander Leacy
- Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada
| | - Phuc H Pham
- Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada
| | - Yanlong Pei
- Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada
| | - Leonardo Susta
- Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada.
| | - Sarah K Wootton
- Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada.
| | - Darwyn Kobasa
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada.
| |
Collapse
|
|
10
|
Sánchez D, Cesarman-Maus G, Romero L, Sánchez-Verin R, Vail D, Guadarrama M, Pelayo R, Sarmiento-Silva RE, Lizano M. The NDV-MLS as an Immunotherapeutic Strategy for Breast Cancer: Proof of Concept in Female Companion Dogs with Spontaneous Mammary Cancer. Viruses 2024; 16:372. [PMID: 38543739 PMCID: PMC10974497 DOI: 10.3390/v16030372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/13/2024] [Accepted: 02/25/2024] [Indexed: 05/23/2024] Open
Abstract
The absence of tumor-infiltrating lymphocytes negatively impacts the response to chemotherapy and prognosis in all subtypes of breast cancer. Therapies that stimulate a proinflammatory environment may help improve the response to standard treatments and also to immunotherapies such as checkpoint inhibitors. Newcastle disease virus (NDV) shows oncolytic activity, as well as immune modulating potential, in the treatment of breast cancer in vitro and in vivo; however, its potential to enhance tumor-infiltrating immune cells in breast cancer has yet to be evaluated. Since spontaneous canine mammary tumors represent a translational model of human breast cancer, we conducted this proof-of-concept study, which could provide a rationale for further investigating NDV-MLS as immunotherapy for mammary cancer. Six female companion dogs with spontaneous mammary cancer received a single intravenous and intratumoral injection of oncolytic NDV-MLS. Immune cell infiltrates were evaluated by histology and immunohistochemistry in the stromal, intratumoral, and peritumoral compartments on day 6 after viral administration. Increasing numbers of immune cells were documented post-viral treatment, mainly in the peritumoral compartment, where plasma cells and CD3+ and CD3-/CD79- lymphocytes predominated. Viral administration was well tolerated, with no significant adverse events. These findings support additional research on the use of NDV-MLS immunotherapy for mammary cancer.
Collapse
Affiliation(s)
- Diana Sánchez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- NorthStar VETS, Veterinary Emergency Trauma & Specialty Centers, Robbinsville, NJ 08691, USA
| | - Gabriela Cesarman-Maus
- Departamento de Hematología, Instituto Nacional de Cancerología, Mexico City 14080, Mexico;
| | - Laura Romero
- Departamento de Patología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (L.R.); (M.G.)
| | | | - David Vail
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA;
| | - Marina Guadarrama
- Departamento de Patología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (L.R.); (M.G.)
| | - Rosana Pelayo
- Unidad de Educación e Investigación, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico;
- Centro de Investigación Biomédica de Oriente, CIBIOR, Instituto Mexicano del Seguro Social, Puebla 06720, Mexico
| | - Rosa Elena Sarmiento-Silva
- Departamento de Microbiología e Inmunología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Marcela Lizano
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| |
Collapse
|
|
11
|
Rogerson T, Xi G, Ampey A, Borman J, Jaroudi S, Pappas D, Linke T. Purification of a recombinant oncolytic virus from clarified cell culture media by anion exchange monolith chromatography. Electrophoresis 2023; 44:1923-1933. [PMID: 37400365 DOI: 10.1002/elps.202200270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/20/2023] [Accepted: 05/24/2023] [Indexed: 07/05/2023]
Abstract
The use of viral vectors for vaccine, gene therapy, and oncolytic virotherapy applications has received increased attention in recent years. Large-scale purification of viral vector-based biotherapeutics still presents a significant technical challenge. Chromatography is the primary tool for the purification of biomolecules in the biotechnology industry; however, the majority of chromatography resins currently available have been designed for the purification of proteins. In contrast, convective interaction media monoliths are chromatographic supports that have been designed and successfully utilized for the purification of large biomolecules, including viruses, viruslike particles, and plasmids. We present a case study on the development of a purification method for recombinant Newcastle disease virus directly from clarified cell culture media using strong anion exchange monolith technology (CIMmultus QA, BIA Separations). Resin screening studies showed at least 10 times higher dynamic binding capacity of CIMmultus QA compared to traditional anion exchange chromatography resins. Design of experiments was used to demonstrate a robust operating window for the purification of recombinant virus directly from clarified cell culture without any further pH or conductivity adjustment of the load material. The capture step was successfully scaled up from 1 mL CIMmultus QA columns to the 8 L column scale and achieved a greater than 30-fold reduction in process volume. Compared to the load material, total host cell proteins were reduced by more than 76%, and residual host cell DNA by more than 57% in the elution pool, respectively. Direct loading of clarified cell culture onto a high-capacity monolith stationary phase makes convective flow chromatography an attractive alternative to centrifugation or TFF-based virus purification procedures.
Collapse
Affiliation(s)
- Troy Rogerson
- Process & Analytical Sciences, BioPharmaceutical Development, BioPharmaceutical Development R&D, AstraZeneca LLC, Gaithersburg, Maryland, USA
| | - Guoling Xi
- Process & Analytical Sciences, BioPharmaceutical Development, BioPharmaceutical Development R&D, AstraZeneca LLC, Gaithersburg, Maryland, USA
| | - Amanda Ampey
- Process & Analytical Sciences, BioPharmaceutical Development, BioPharmaceutical Development R&D, AstraZeneca LLC, Gaithersburg, Maryland, USA
| | - Jon Borman
- Process & Analytical Sciences, BioPharmaceutical Development, BioPharmaceutical Development R&D, AstraZeneca LLC, Gaithersburg, Maryland, USA
| | - Sally Jaroudi
- Process & Analytical Sciences, BioPharmaceutical Development, BioPharmaceutical Development R&D, AstraZeneca LLC, Gaithersburg, Maryland, USA
| | - Dan Pappas
- Manufacturing Sciences, BioPharmaceutical Development, Biopharmaceuticals R&D, AstraZeneca LLC, Gaithersburg, Maryland, USA
| | - Thomas Linke
- Process & Analytical Sciences, BioPharmaceutical Development, BioPharmaceutical Development R&D, AstraZeneca LLC, Gaithersburg, Maryland, USA
| |
Collapse
|
|
12
|
de Swart RL, Belov GA. Advantages and challenges of Newcastle disease virus as a vector for respiratory mucosal vaccines. Curr Opin Virol 2023; 62:101348. [PMID: 37591130 DOI: 10.1016/j.coviro.2023.101348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 07/18/2023] [Indexed: 08/19/2023]
Abstract
Newcastle disease virus (NDV) is an avian pathogen with an unsegmented negative-strand RNA genome. Properties such as the ease of genome modification, respiratory tract tropism, and self-limiting replication in mammals make NDV an attractive vector for vaccine development. Experimental NDV-based vaccines against multiple human and animal pathogens elicited both systemic and mucosal immune responses and were protective in preclinical animal studies, but their real-life efficacy remains to be demonstrated. Only recently, the first results of clinical trials of NDV-based vaccines against SARS-CoV-2 became available, highlighting the challenges that need to be overcome to fully realize the potential of NDV as a platform for the rapid development of economically affordable and effective mucosal vaccines.
Collapse
Affiliation(s)
- Rik L de Swart
- Department of Virology, Wageningen Bioveterinary Research, Lelystad, the Netherlands.
| | - George A Belov
- Department of Veterinary Medicine and Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA.
| |
Collapse
|
|
13
|
Jung B, An YH, Jang SH, Ryu G, Jung S, Kim S, Kim C, Jang H. The tumor suppressive effect and apoptotic mechanism of TRAIL gene-containing recombinant NDV in TRAIL-resistant colorectal cancer HT-29 cells and TRAIL-nonresistant HCT116 cells, with each cell bearing a mouse model. Cancer Med 2023; 12:20380-20395. [PMID: 37843231 PMCID: PMC10652305 DOI: 10.1002/cam4.6622] [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: 05/11/2023] [Revised: 09/12/2023] [Accepted: 09/29/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND TRAIL is an anticancer drug that induces cancer cell apoptosis by interacting with death receptors (DRs). However, owing to low cell-surface expression of DRs, certain colorectal cancer (CRC) cells resist TRAIL-induced apoptosis. Newcastle disease virus (NDV) infection can elevate DR protein expression in cancer cells, potentially influencing their TRAIL sensitivity. However, the precise mechanism by which NDV infection modulates DR expression and impacts TRAIL sensitivity in cancer cells remains unknown. METHODS Herein, we developed nonpathogenic NDV VG/GA strain-based recombinant NDV (rNDV) and TRAIL gene-containing rNDV (rNDV-TRAIL). We observed that viral infections lead to increased DR and TRAIL expressions and activate signaling proteins involved in intrinsic and extrinsic apoptosis pathways. Experiments were conducted in vitro using TRAIL-resistant CRC cells (HT-29) and nonresistant CRC cells (HCT116) and in vivo using relevant mouse models. RESULTS rNDV-TRAIL was found to exhibit better apoptotic efficacy than rNDV in CRC cells. Notably, rNDV-TRAIL had the stronger cancer cell-killing effect in TRAIL-resistant CRC cells. Western blot analyses showed that both rNDV and rNDV-TRAIL infections activate signaling proteins involved in the intrinsic and extrinsic apoptotic pathways. Notably, rNDV-TRAIL promotes concurrent intrinsic and extrinsic signal transduction in both HCT-116 and HT-29 cells. CONCLUSIONS Therefore, rNDV-TRAIL infection effectively enhances DR expression in DR-depressed HT-29 cells. Moreover, the TRAIL protein expressed by rNDV-TRAIL effectively interacts with DR, leading to enhanced apoptosis in TRAIL-resistant HT-29 cells. Therefore, rNDV-TRAIL has potential as a promising therapeutic approach for treating TRAIL-resistant cancers.
Collapse
Affiliation(s)
| | | | - Sung Hoon Jang
- Graduate School of Medical Science, College of medicineYonsei UniversitySeoulRepublic of Korea
| | | | | | - Seonhee Kim
- Department of Physiology & Medical Science, College of MedicineChungnam National UniversityDaejeonRepublic of Korea
| | - Cuk‐Seong Kim
- Department of Physiology & Medical Science, College of MedicineChungnam National UniversityDaejeonRepublic of Korea
| | - Hyun Jang
- Libentech Co. LTDDaejeonRepublic of Korea
| |
Collapse
|
|
14
|
Onnockx S, Baldo A, Pauwels K. Oncolytic Viruses: An Inventory of Shedding Data from Clinical Trials and Elements for the Environmental Risk Assessment. Vaccines (Basel) 2023; 11:1448. [PMID: 37766125 PMCID: PMC10535390 DOI: 10.3390/vaccines11091448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Attenuated and/or genetically modified oncolytic viruses (OV) gain increasing interest as a promising approach for cancer therapy. Beside the assessment of subject safety, quality and efficacy aspects of medicinal products for human use, genetically modified viruses are also governed by EU regulatory frameworks requiring an environmental risk assessment (ERA). An important element to be assessed as part of the ERA is the incidence of exposure to OV of individuals, other than the trial subjects, and the environment. The evidence-based evaluation of shedding data is considered to be decisive in that context, as it may impact the OV capacity to be transmitted. This is particularly true for OV still able to (conditionally) replicate as opposed to replication-defective viral vectors commonly used in gene therapy or vaccination. To our knowledge, this article presents the most extensive and up-to-date review of shedding data reported with OV employed in clinics. Besides the identification of a topical need for improving the collection of shedding data, this article aims at providing an aid to the design of an appropriate shedding study, thereby relying on and further complementing principles described in existing guidelines issued by European and international institutions.
Collapse
Affiliation(s)
- Sheela Onnockx
- Sciensano, Service Biosafety and Biotechnology, Rue Juliette Wytsmanstraat 14, B-1050 Brussels, Belgium; (A.B.); (K.P.)
| | | | | |
Collapse
|
|
15
|
Khalid Z, Coco S, Ullah N, Pulliero A, Cortese K, Varesano S, Orsi A, Izzotti A. Anticancer Activity of Measles-Mumps-Rubella MMR Vaccine Viruses against Glioblastoma. Cancers (Basel) 2023; 15:4304. [PMID: 37686579 PMCID: PMC10486717 DOI: 10.3390/cancers15174304] [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: 07/28/2023] [Revised: 08/25/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
BACKGROUND Oncolytic viruses (OVs) have been utilized since 1990s for targeted cancer treatment. Our study examined the Measles-Mumps-Rubella (MMR) vaccine's cancer-killing potency against Glioblastoma (GBM), a therapy-resistant, aggressive cancer type. METHODOLOGY We used GBM cell lines, primary GBM cells, and normal mice microglial cells, to assess the MMR vaccine's efficacy through cell viability, cell cycle analysis, intracellular viral load via RT-PCR, and Transmission Electron Microscopy (TEM). RESULTS After 72 h of MMR treatment, GBM cell lines and primary GBM cells exhibited significant viability reduction compared to untreated cells. Conversely, normal microglial cells showed only minor changes in viability and morphology. Intracellular viral load tests indicated GBM cells' increased sensitivity to MMR viruses compared to normal cells. The cell cycle study also revealed measles and mumps viruses' crucial role in cytopathic effects, with the rubella virus causing cell cycle arrest. CONCLUSION Herein the reported results demonstrate the anti-cancer activity of the MMR vaccine against GBM cells. Accordingly, the MMR vaccine warrants further study as a potential new tool for GBM therapy and relapse prevention. Therapeutic potential of the MMR vaccine has been found to be promising in earlier studies as well.
Collapse
Affiliation(s)
- Zumama Khalid
- Department of Health Sciences, University of Genova, Via Pastore 1, 16132 Genoa, Italy; (Z.K.); (N.U.); (A.P.); (A.O.)
| | - Simona Coco
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy; (S.C.); (S.V.)
| | - Nadir Ullah
- Department of Health Sciences, University of Genova, Via Pastore 1, 16132 Genoa, Italy; (Z.K.); (N.U.); (A.P.); (A.O.)
| | - Alessandra Pulliero
- Department of Health Sciences, University of Genova, Via Pastore 1, 16132 Genoa, Italy; (Z.K.); (N.U.); (A.P.); (A.O.)
| | - Katia Cortese
- Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy;
| | - Serena Varesano
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy; (S.C.); (S.V.)
| | - Andrea Orsi
- Department of Health Sciences, University of Genova, Via Pastore 1, 16132 Genoa, Italy; (Z.K.); (N.U.); (A.P.); (A.O.)
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy; (S.C.); (S.V.)
| | - Alberto Izzotti
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy; (S.C.); (S.V.)
- Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy;
| |
Collapse
|
|
16
|
Zhu X, Fan C, Xiong Z, Chen M, Li Z, Tao T, Liu X. Development and application of oncolytic viruses as the nemesis of tumor cells. Front Microbiol 2023; 14:1188526. [PMID: 37440883 PMCID: PMC10335770 DOI: 10.3389/fmicb.2023.1188526] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/18/2023] [Indexed: 07/15/2023] Open
Abstract
Viruses and tumors are two pathologies that negatively impact human health, but what occurs when a virus encounters a tumor? A global consensus among cancer patients suggests that surgical resection, chemotherapy, radiotherapy, and other methods are the primary means to combat cancer. However, with the innovation and development of biomedical technology, tumor biotherapy (immunotherapy, molecular targeted therapy, gene therapy, oncolytic virus therapy, etc.) has emerged as an alternative treatment for malignant tumors. Oncolytic viruses possess numerous anti-tumor properties, such as directly lysing tumor cells, activating anti-tumor immune responses, and improving the tumor microenvironment. Compared to traditional immunotherapy, oncolytic virus therapy offers advantages including high killing efficiency, precise targeting, and minimal side effects. Although oncolytic virus (OV) therapy was introduced as a novel approach to tumor treatment in the 19th century, its efficacy was suboptimal, limiting its widespread application. However, since the U.S. Food and Drug Administration (FDA) approved the first OV therapy drug, T-VEC, in 2015, interest in OV has grown significantly. In recent years, oncolytic virus therapy has shown increasingly promising application prospects and has become a major research focus in the field of cancer treatment. This article reviews the development, classification, and research progress of oncolytic viruses, as well as their mechanisms of action, therapeutic methods, and routes of administration.
Collapse
Affiliation(s)
- Xiao Zhu
- Zhejiang Provincial People's Hospital Affiliated to Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
- Department of Biological and Chemical Sciences, New York Institute of Technology—Manhattan Campus, New York, NY, United States
| | - Chenyang Fan
- Department of Clinical Medicine, Medicine and Technology, School of Zunyi Medical University, Zunyi, China
| | - Zhuolong Xiong
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Mingwei Chen
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital(Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Tao Tao
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Xiuqing Liu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| |
Collapse
|
|
17
|
Chang R, Gulley JL, Fong L. Vaccinating against cancer: getting to prime time. J Immunother Cancer 2023; 11:jitc-2022-006628. [PMID: 37286302 DOI: 10.1136/jitc-2022-006628] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2023] [Indexed: 06/09/2023] Open
Abstract
Immunotherapies, such as immune checkpoint inhibitors, cellular therapies, and T-cell engagers, have fundamentally changed our approach to treating cancer. However, successes with cancer vaccines have been more difficult to realize. While vaccines against specific viruses have been widely adopted to prevent the development of cancer, only two vaccines can improve survival in advanced disease: sipuleucel-T and talimogene laherparepvec. These represent the two approaches that have the most traction: vaccinating against cognate antigen and priming responses using tumors in situ. Here, we review the challenges and opportunities researchers face in developing therapeutic vaccines for cancer.
Collapse
Affiliation(s)
- Ryan Chang
- Hematology/Oncology, University of California, San Francisco, California, USA
| | - James L Gulley
- NCI, National Institutes of Health, Bethesda, Maryland, USA
| | - Lawrence Fong
- Hematology/Oncology, University of California, San Francisco, California, USA
| |
Collapse
|
|
18
|
Duan S, Wang S, Qiao L, Yu X, Wang N, Chen L, Zhang X, Zhao X, Liu H, Wang T, Wu Y, Li N, Liu F. Oncolytic Virus-Driven Biotherapies from Bench to Bedside. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2206948. [PMID: 36879416 DOI: 10.1002/smll.202206948] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/17/2023] [Indexed: 06/08/2023]
Abstract
With advances in cancer biology and an ever-deepening understanding of molecular virology, oncolytic virus (OV)-driven therapies have developed rapidly and become a promising alternative to traditional cancer therapies. In recent years, satisfactory results for oncolytic virus therapy (OVT) are achieved at both the cellular and organismal levels, and efforts are being increasingly directed toward clinical trials. Unfortunately, OVT remains ineffective in these trials, especially when performed using only a single OV reagent. In contrast, integrated approaches, such as using immunotherapy, chemotherapy, or radiotherapy, alongside OVT have demonstrated considerable efficacy. The challenges of OVT in clinical efficacy include the restricted scope of intratumoral injections and poor targeting of intravenous administration. Further optimization of OVT delivery is needed before OVs become a viable therapy for tumor treatment. In this review, the development process and antitumor mechanisms of OVs are introduced. The advances in OVT delivery routes to provide perspectives and directions for the improvement of OVT delivery are highlighted. This review also discusses the advantages and limitations of OVT monotherapy and combination therapy through the lens of recent clinical trials and aims to chart a course toward safer and more effective OVT strategies.
Collapse
Affiliation(s)
- Shijie Duan
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Shuhang Wang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lei Qiao
- Colorectal and Henia Minimally Invasive Surgery Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xinbo Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Nan Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Liting Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xinyuan Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xu Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Hongyu Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Tianye Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ying Wu
- Phase I Clinical Trials Center, The First Hospital of China Medical University, Department of General Practice, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ning Li
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Funan Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Phase I Clinical Trials Center, The First Hospital of China Medical University, Shenyang, 110001, China
| |
Collapse
|
|
19
|
Kanaya N, Kitamura Y, Vazquez ML, Franco A, Chen KS, van Schaik TA, Farzani TA, Borges P, Ichinose T, Seddiq W, Kuroda S, Boland G, Jahan N, Fisher D, Wakimoto H, Shah K. Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas. Sci Transl Med 2023; 15:eade8732. [PMID: 37256936 PMCID: PMC10799631 DOI: 10.1126/scitranslmed.ade8732] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 02/10/2023] [Accepted: 05/10/2023] [Indexed: 06/02/2023]
Abstract
Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1KO) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAFV600E/PTEN-/- and BRAFV600E/wt/PTEN-/- mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell- and T cell-mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SCN1KO-releasing GM-CSF and single-chain variable fragment anti-PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.
Collapse
Affiliation(s)
- Nobuhiko Kanaya
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yohei Kitamura
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Maria Lopez Vazquez
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Arnaldo Franco
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Kok-Siong Chen
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Thijs A. van Schaik
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Touraj Aligholipour Farzani
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Paulo Borges
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Toru Ichinose
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Waleed Seddiq
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Shinji Kuroda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Genevieve Boland
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Nusrat Jahan
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - David Fisher
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Hiroaki Wakimoto
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Khalid Shah
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| |
Collapse
|
|
20
|
Rondon L, Fu R, Patel MR. Success of Checkpoint Blockade Paves the Way for Novel Immune Therapy in Malignant Pleural Mesothelioma. Cancers (Basel) 2023; 15:2940. [PMID: 37296902 PMCID: PMC10251855 DOI: 10.3390/cancers15112940] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/18/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is a malignancy associated with asbestos exposure and is typically categorized as an orphan disease. Recent developments in immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies, specifically with agents nivolumab and ipilimumab, have demonstrated an improvement in overall survival over the previous standard chemotherapy leading to their FDA-approval as first-line therapy for unresectable disease. For quite some time, it has been known that these proteins are not the only ones that function as immune checkpoints in human biology, and the hypothesis that MPM is an immunogenic disease has led to an expanding number of studies investigating alternative checkpoint inhibitors and novel immunotherapy for this malignancy. Early trials are also supporting the notion that therapies that target biological molecules on T cells, cancer cells, or that trigger the antitumor activity of other immune cells may represent the future of MPM treatment. Moreover, mesothelin-targeted therapies are thriving in the field, with forthcoming results from multiple trials signaling an improvement in overall survival when combined with other immunotherapy agents. The following manuscript will review the current state of immune therapy for MPM, explore the knowledge gaps in the field, and discuss ongoing novel immunotherapeutic research in early clinical trials.
Collapse
Affiliation(s)
- Lizbeth Rondon
- Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55404, USA; (L.R.); (R.F.)
| | - Roberto Fu
- Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55404, USA; (L.R.); (R.F.)
| | - Manish R. Patel
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| |
Collapse
|
|
21
|
Huang J, Zheng T, Liang Y, Qin Y, Wu X, Fan X. Transcriptome Analysis of Natural Killer Cells in Response to Newcastle Disease Virus Infected Hepatocellular Carcinoma Cells. Genes (Basel) 2023; 14:genes14040888. [PMID: 37107646 PMCID: PMC10138298 DOI: 10.3390/genes14040888] [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: 02/24/2023] [Revised: 03/27/2023] [Accepted: 03/31/2023] [Indexed: 04/29/2023] Open
Abstract
When tumor cells are infected by the Newcastle disease virus (NDV), the lysis of tumor cells by natural killer (NK) cells is enhanced, which may be related to the enhanced NK cell activation effect. To better understand the intracellular molecular mechanisms involved in NK cell activation, the transcriptome profiles of NK cells stimulated by NDV-infected hepatocellular carcinoma (HCC) cells (NDV group) and control (NC group, NK cells stimulated by HCC cells) were analyzed. In total, we identified 1568 differentially expressed genes (DEGs) in the NK cells of the NDV group compared to the control, including 1389 upregulated and 179 downregulated genes. Functional analysis showed that DEGs were enriched in the immune system, signal transmission, cell growth, cell death, and cancer pathways. Notably, 9 genes from the IFN family were specifically increased in NK cells upon NDV infection and identified as potential prognosis markers for patients with HCC. A qRT-PCR experiment was used to confirm the differential expression of IFNG and the other 8 important genes. The results of this study will improve our understanding of the molecular mechanisms of NK cell activation.
Collapse
Affiliation(s)
- Juanjuan Huang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China
- Department of Microbiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Tingting Zheng
- Department of Microbiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Ying Liang
- Department of Microbiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
- Key Laboratory of Basic Research on Regional Disease, Education Department of Guangxi, Guangxi Medical University, Nanning 530021, China
| | - Ying Qin
- Department of Microbiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Xing Wu
- Department of Microbiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Xiaohui Fan
- Department of Microbiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
- Key Laboratory of Basic Research on Regional Disease, Education Department of Guangxi, Guangxi Medical University, Nanning 530021, China
| |
Collapse
|
|
22
|
Extracellular Vesicles: a Trojan Horse Delivery Method for Systemic Administration of Oncolytic Viruses. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2023. [DOI: 10.1007/s40883-023-00295-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
|
|
23
|
Ma R, Li Z, Chiocca EA, Caligiuri MA, Yu J. The emerging field of oncolytic virus-based cancer immunotherapy. Trends Cancer 2023; 9:122-139. [PMID: 36402738 PMCID: PMC9877109 DOI: 10.1016/j.trecan.2022.10.003] [Citation(s) in RCA: 128] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/18/2022]
Abstract
Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs are multifaceted tumor killers. They directly lyse tumor cells while sparing normal cells, and indirectly potentiate antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment. However, some limitations, such as limited penetration of OVs into tumors, short persistence, and the host antiviral immune response, are impeding the broad translation of oncolytic virotherapy into the clinic. If these challenges can be overcome, combination therapies, such as OVs plus immune checkpoint blockade (ICB), chimeric antigen receptor (CAR) T cells, or CAR natural killer (NK) cells, may provide powerful therapeutic platforms in the clinic.
Collapse
Affiliation(s)
- Rui Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Zhenlong Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - E Antonio Chiocca
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute, Los Angeles, CA 91010, USA.
| |
Collapse
|
|
24
|
Lundstrom K. Gene Therapy Cargoes Based on Viral Vector Delivery. Curr Gene Ther 2023; 23:111-134. [PMID: 36154608 DOI: 10.2174/1566523222666220921112753] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/13/2022] [Accepted: 08/05/2022] [Indexed: 11/22/2022]
Abstract
Viral vectors have been proven useful in a broad spectrum of gene therapy applications due to their possibility to accommodate foreign genetic material for both local and systemic delivery. The wide range of viral vectors has enabled gene therapy applications for both acute and chronic diseases. Cancer gene therapy has been addressed by the delivery of viral vectors expressing anti-tumor, toxic, and suicide genes for the destruction of tumors. Delivery of immunostimulatory genes such as cytokines and chemokines has also been applied for cancer therapy. Moreover, oncolytic viruses specifically replicating in and killing tumor cells have been used as such for tumor eradication or in combination with tumor killing or immunostimulatory genes. In a broad meaning, vaccines against infectious diseases and various cancers can be considered gene therapy, which has been highly successful, not the least for the development of effective COVID-19 vaccines. Viral vector-based gene therapy has also demonstrated encouraging and promising results for chronic diseases such as severe combined immunodeficiency (SCID), muscular dystrophy, and hemophilia. Preclinical gene therapy studies in animal models have demonstrated proof-of-concept for a wide range of disease indications. Clinical evaluation of drugs and vaccines in humans has showed high safety levels, good tolerance, and therapeutic efficacy. Several gene therapy drugs such as the adenovirus-based drug Gendicine® for non-small-cell lung cancer, the reovirus-based drug Reolysin® for ovarian cancer, lentivirus-based treatment of SCID-X1 disease, and the rhabdovirus-based vaccine Ervebo against Ebola virus disease, and adenovirus-based vaccines against COVID-19 have been developed.
Collapse
|
|
25
|
Ortega-Rivera OA, Gallegos-Alcalá P, Jiménez M, Quintanar JL, Torres-Juarez F, Rivas-Santiago B, del Toro-Arreola S, Salinas E. Inhibition of Tumor Growth and Metastasis by Newcastle Disease Virus Strain P05 in a Breast Cancer Mouse Model. J Breast Cancer 2023; 26:186-200. [PMID: 37051644 PMCID: PMC10139849 DOI: 10.4048/jbc.2023.26.e9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/16/2022] [Accepted: 01/24/2023] [Indexed: 02/25/2023] Open
Abstract
PURPOSE Conventional therapies and surgery remain the standard treatment for breast cancer. However, combating the eventual development of metastasis is still a challenge. Newcastle disease virus (NDV) is one of the various species of viruses under clinical evaluation as a vector for oncolytic, gene-, and immune-stimulating therapies. The purpose of this study was to evaluate the antitumor activity of a recombinant NDV (rNDV-P05) in a breast cancer murine model. METHODS Tumors were induced by injecting the cellular suspension (4T1 cell line) subcutaneously. The virus strain P05 was applied three times at intervals of seven days, starting seven days after tumor induction, and was completed 21 days later. Determination of tumor weight, spleen index, and lung metastasis were done after sacrificing the mice. Serum levels of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, and TNF-related apoptosis-inducing ligand (TRAIL) were quantified by enzyme-linked immunosorbent assay. CD8+ infiltrated cells were analyzed by immunofluorescence. RESULTS rNDV-P05 showed a route-of-administration-dependent effect, demonstrating that the systemic administration of the virus significantly reduces the tumor mass and volume, spleen index, and abundance of metastatic clonogenic colonies in lung tissue, and increases the inhibition rate of the tumor. The intratumoral administration of rNDV-P05 was ineffective for all the parameters evaluated. Antitumor and antimetastatic capability of rNDV-P05 is mediated, at least partially, through its immune-stimulatory effect on the upregulation of TNF-α, TRAIL, IFN-α, and IFN-γ, and its ability to recruit CD8+ T cells into tumor tissue. CONCLUSION Systemic treatment with rNDV-P05 decreases the tumoral parameters in the breast cancer murine model.
Collapse
Affiliation(s)
- Oscar Antonio Ortega-Rivera
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
- Department of NanoEngineering, University of California San Diego, La Jolla, USA
| | - Pamela Gallegos-Alcalá
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
| | - Mariela Jiménez
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
| | - J. Luis Quintanar
- Department of Physiology and Pharmacology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
| | - Flor Torres-Juarez
- Medical Research Unit-Zacatecas, Mexican Institute for Social Security (IMSS), Zacatecas, Mexico
| | - Bruno Rivas-Santiago
- Medical Research Unit-Zacatecas, Mexican Institute for Social Security (IMSS), Zacatecas, Mexico
| | - Susana del Toro-Arreola
- Department of Physiology, CUCS, University of Guadalajara, Guadalajara, Mexico
- Institute of Research in Chronic Degenerative Diseases, Department of Molecular Biology and Genomic, CUCS, University of Guadalajara, Guadalajara, Mexico
| | - Eva Salinas
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
| |
Collapse
|
|
26
|
Omole RK, Oluwatola O, Akere MT, Eniafe J, Agboluaje EO, Daramola OB, Ayantunji YJ, Omotade TI, Torimiro N, Ayilara MS, Adeyemi OI, Salinsile OS. Comprehensive assessment on the applications of oncolytic viruses for cancer immunotherapy. Front Pharmacol 2022; 13:1082797. [PMID: 36569326 PMCID: PMC9772532 DOI: 10.3389/fphar.2022.1082797] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
The worldwide burden of cancers is increasing at a very high rate, including the aggressive and resistant forms of cancers. Certain levels of breakthrough have been achieved with the conventional treatment methods being used to treat different forms of cancers, but with some limitations. These limitations include hazardous side effects, destruction of non-tumor healthy cells that are rapidly dividing and developing, tumor resistance to anti-cancer drugs, damage to tissues and organs, and so on. However, oncolytic viruses have emerged as a worthwhile immunotherapeutic option for the treatment of different types of cancers. In this treatment approach, oncolytic viruses are being modeled to target cancer cells with optimum cytotoxicity and spare normal cells with optimal safety, without the oncolytic viruses themselves being killed by the host immune defense system. Oncolytic viral infection of the cancer cells are also being genetically manipulated (either by removal or addition of certain genes into the oncolytic virus genome) to make the tumor more visible and available for attack by the host immune cells. Hence, different variants of these viruses are being developed to optimize their antitumor effects. In this review, we examined how grave the burden of cancer is on a global level, particularly in sub-Saharan Africa, major conventional therapeutic approaches to the treatment of cancer and their individual drawbacks. We discussed the mechanisms of action employed by these oncolytic viruses and different viruses that have found their relevance in the fight against various forms of cancers. Some pre-clinical and clinical trials that involve oncolytic viruses in cancer management were reported. This review also examined the toxicity and safety concerns surrounding the adoption of oncolytic viro-immunotherapy for the treatment of cancers and the likely future directions for researchers and general audience who wants updated information.
Collapse
Affiliation(s)
- Richard Kolade Omole
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria,Microbiology Unit, Department of Applied Sciences, Osun State College of Technology, Esa-Oke, Nigeria,*Correspondence: Richard Kolade Omole,
| | - Oluwaseyi Oluwatola
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States,Department of Immunology, Moffit Cancer Center, Tampa, FL, United States
| | - Millicent Tambari Akere
- Department of Medicinal and Biological Chemistry, University of Toledo, Toledo, OH, United States
| | - Joseph Eniafe
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, United States
| | | | | | - Yemisi Juliet Ayantunji
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria,Advanced Space Technology Applications Laboratory, Cooperative Information Network, National Space Research and Development Agency, Ile-Ife, Nigeria
| | | | - Nkem Torimiro
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Modupe Stella Ayilara
- Food Security and Safety Focus Area, Faculty of Natural and Agricultural Sciences, North-West University, Mmabatho, South Africa
| | - Oluwole Isaac Adeyemi
- Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
| | | |
Collapse
|
|
27
|
Li SJ, Sun ZJ. Fueling immune checkpoint blockade with oncolytic viruses: Current paradigms and challenges ahead. Cancer Lett 2022; 550:215937. [DOI: 10.1016/j.canlet.2022.215937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/20/2022] [Accepted: 09/29/2022] [Indexed: 11/29/2022]
|
|
28
|
Baiocchi L, Francis H, Alpini G. Therapeutic Use of Viruses: Newcastle Disease Virus HK84 Oncolytic Treatment for Hepatocellular Carcinoma. J Clin Transl Hepatol 2022; 10:783-785. [PMID: 36304496 PMCID: PMC9547249 DOI: 10.14218/jcth.2022.00229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/16/2022] [Accepted: 07/04/2022] [Indexed: 12/04/2022] Open
Affiliation(s)
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| |
Collapse
|
|
29
|
Tang C, Li L, Mo T, Na J, Qian Z, Fan D, Sun X, Yao M, Pan L, Huang Y, Zhong L. Oncolytic viral vectors in the era of diversified cancer therapy: from preclinical to clinical. Clin Transl Oncol 2022; 24:1682-1701. [PMID: 35612653 PMCID: PMC9131313 DOI: 10.1007/s12094-022-02830-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/21/2022] [Indexed: 12/19/2022]
Abstract
With the in-depth research and wide application of immunotherapy recently, new therapies based on oncolytic viruses are expected to create new prospects for cancer treatment via eliminating the suppression of the immune system by tumors. Currently, an increasing number of viruses are developed and engineered, and various virus vectors based on effectively stimulating human immune system to kill tumor cells have been approved for clinical treatment. Although the virus can retard the proliferation of tumor cells, the choice of oncolytic viruses in biological cancer therapy is equally critical given their therapeutic efficacy, safety and adverse effects. Moreover, previously known oncolytic viruses have not been systematically classified. Therefore, in this review, we summarized and distinguished the characteristics of several common types of oncolytic viruses: herpes simplex virus, adenovirus, measles virus, Newcastle disease virus, reovirus and respiratory syncytial virus. Subsequently, we outlined that these oncolytic viral vectors have been transformed from preclinical studies in combination with immunotherapy, radiotherapy, chemotherapy, and nanoparticles into clinical therapeutic strategies for various advanced solid malignancies or circulatory system cancers.
Collapse
Affiliation(s)
- Chao Tang
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Lan Li
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Tong Mo
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jintong Na
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhangbo Qian
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Dianfa Fan
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Xinjun Sun
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Min Yao
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Lina Pan
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yong Huang
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China.
| | - Liping Zhong
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China.
| |
Collapse
|
|
30
|
Huang F, Dai C, Zhang Y, Zhao Y, Wang Y, Ru G. Development of Molecular Mechanisms and Their Application on Oncolytic Newcastle Disease Virus in Cancer Therapy. Front Mol Biosci 2022; 9:889403. [PMID: 35860357 PMCID: PMC9289221 DOI: 10.3389/fmolb.2022.889403] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer is caused by the destruction or mutation of cellular genetic materials induced by environmental or genetic factors. It is defined by uncontrolled cell proliferation and abnormality of the apoptotic pathways. The majority of human malignancies are characterized by distant metastasis and dissemination. Currently, the most common means of cancer treatment include surgery, radiotherapy, and chemotherapy, which usually damage healthy cells and cause toxicity in patients. Targeted therapy is an effective tumor treatment method with few side effects. At present, some targeted therapeutic drugs have achieved encouraging results in clinical studies, but finding an effective solution to improve the targeting and delivery efficiency of these drugs remains a challenge. In recent years, oncolytic viruses (OVs) have been used to direct the tumor-targeted therapy or immunotherapy. Newcastle disease virus (NDV) is a solid oncolytic agent capable of directly killing tumor cells and increasing tumor antigen exposure. Simultaneously, NDV can trigger the proliferation of tumor-specific immune cells and thus improve the therapeutic efficacy of NDV in cancer. Based on NDV’s inherent oncolytic activity and the stimulation of antitumor immune responses, the combination of NDV and other tumor therapy approaches can improve the antitumor efficacy while reducing drug toxicity, indicating a broad application potential. We discussed the biological properties of NDV, the antitumor molecular mechanisms of oncolytic NDV, and its application in the field of tumor therapy in this review. Furthermore, we presented new insights into the challenges that NDV will confront and suggestions for increasing NDV’s therapeutic efficacy in cancer.
Collapse
Affiliation(s)
- Fang Huang
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Chuanjing Dai
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
| | - Youni Zhang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
- Department of Laboratory Medicine, Tiantai People’s Hospital, Taizhou, China
| | - Yuqi Zhao
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yigang Wang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China
- *Correspondence: Yigang Wang, ; Guoqing Ru,
| | - Guoqing Ru
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Yigang Wang, ; Guoqing Ru,
| |
Collapse
|
|
31
|
de Graaf JF, Huberts M, Groeneveld D, van Nieuwkoop S, van Eijck CHJ, Fouchier RAM, van den Hoogen BG. Comparison between intratumoral and intravenously administered oncolytic virus therapy with Newcastle disease virus in a xenograft murine model for pancreatic adenocarcinoma. Heliyon 2022; 8:e09915. [PMID: 35874055 PMCID: PMC9304737 DOI: 10.1016/j.heliyon.2022.e09915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/29/2022] [Accepted: 07/05/2022] [Indexed: 11/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor clinical prognosis and is usually a metastatic disease. In the last decades, oncolytic viro-immunotherapy has shown a promise as treatment strategy with encouraging results for a variety of tumors. Newcastle Disease Virus (NDV) is an oncolytic virus which selectively infects and damages tumors either by directly killing tumor cells or by promoting an anti-tumor immune response. Several studies have demonstrated that NDV strains with a multi-basic cleavage site (MBCS) in the fusion protein (F) have increased anti-tumor efficacy upon intratumoral injection in murine tumor models. However, intravenous injections, in which the oncolytic virus spreads systemically, could be more beneficial to treat metastasized PDAC in addition to the primary tumor. In this study, we compared the oncolytic efficacy and safety of intratumoral and intravenous injections with NDV containing an MBCS in F (NDV F3aa) in an immune deficient murine xenograft (BxPC3) model for PDAC. In this model, both intratumoral and intravenous injections with NDV F3aa induced anti-tumor efficacy as measured at 10 days after the first injection. Upon intravenous injection virus was detected in some of the tumors, indicating the systemic spread of the virus. Upon both treatments, mice did not display weight loss or abnormalities and treated mice did not secrete virus to the environment. These data demonstrate that intravenous injections of NDV F3aa can be applicable to treat metastasized cancers in immune deficient hosts without inflicting adverse effects.
Collapse
Affiliation(s)
| | - Marco Huberts
- Viroscience Department, Erasmus Medical Centrum, Rotterdam, the Netherlands
| | - Daphne Groeneveld
- Viroscience Department, Erasmus Medical Centrum, Rotterdam, the Netherlands
| | | | | | - Ron A M Fouchier
- Viroscience Department, Erasmus Medical Centrum, Rotterdam, the Netherlands
| | | |
Collapse
|
|
32
|
Park HS, Matsuoka Y, Luongo C, Yang L, Santos C, Liu X, Ahlers LRH, Moore IN, Afroz S, Johnson RF, Lafont BAP, Dorward DW, Fischer ER, Martens C, Samal SK, Munir S, Buchholz UJ, Le Nouën C. Intranasal immunization with avian paramyxovirus type 3 expressing SARS-CoV-2 spike protein protects hamsters against SARS-CoV-2. NPJ Vaccines 2022; 7:72. [PMID: 35764659 PMCID: PMC9240059 DOI: 10.1038/s41541-022-00493-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/11/2022] [Indexed: 12/13/2022] Open
Abstract
Current vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are administered parenterally and appear to be more protective in the lower versus the upper respiratory tract. Vaccines are needed that directly stimulate immunity in the respiratory tract, as well as systemic immunity. We used avian paramyxovirus type 3 (APMV3) as an intranasal vaccine vector to express the SARS-CoV-2 spike (S) protein. A lack of pre-existing immunity in humans and attenuation by host-range restriction make APMV3 a vector of interest. The SARS-CoV-2 S protein was stabilized in its prefusion conformation by six proline substitutions (S-6P) rather than the two that are used in most vaccine candidates, providing increased stability. APMV3 expressing S-6P (APMV3/S-6P) replicated to high titers in embryonated chicken eggs and was genetically stable, whereas APMV3 expressing non-stabilized S or S-2P were unstable. In hamsters, a single intranasal dose of APMV3/S-6P induced strong serum IgG and IgA responses to the S protein and its receptor-binding domain, and strong serum neutralizing antibody responses to SARS-CoV-2 isolate WA1/2020 (lineage A). Sera from APMV3/S-6P-immunized hamsters also efficiently neutralized Alpha and Beta variants of concern. Immunized hamsters challenged with WA1/2020 did not exhibit the weight loss and lung inflammation observed in empty-vector-immunized controls; SARS-CoV-2 replication in the upper and lower respiratory tract of immunized animals was low or undetectable compared to the substantial replication in controls. Thus, a single intranasal dose of APMV3/S-6P was highly immunogenic and protective against SARS-CoV-2 challenge, suggesting that APMV3/S-6P is suitable for clinical development.
Collapse
Affiliation(s)
- Hong-Su Park
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yumiko Matsuoka
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Cindy Luongo
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Lijuan Yang
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Celia Santos
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xueqiao Liu
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Laura R H Ahlers
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ian N Moore
- Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Sharmin Afroz
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Reed F Johnson
- SARS-CoV-2 Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bernard A P Lafont
- SARS-CoV-2 Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - David W Dorward
- Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA
| | - Elizabeth R Fischer
- Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA
| | - Craig Martens
- Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA
| | - Siba K Samal
- Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, 20742, USA
| | - Shirin Munir
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ursula J Buchholz
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - Cyril Le Nouën
- RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
33
|
Brown M. Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity. Cancer Treat Res 2022; 183:91-129. [PMID: 35551657 DOI: 10.1007/978-3-030-96376-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Malignant tumors frequently exploit innate immunity to evade immune surveillance. The priming, function, and polarization of antitumor immunity fundamentally depends upon context provided by the innate immune system, particularly antigen presenting cells. Such context is determined in large part by sensing of pathogen specific and damage associated features by pathogen recognition receptors (PRRs). PRR activation induces the delivery of T cell priming cues (e.g. chemokines, co-stimulatory ligands, and cytokines) from antigen presenting cells, playing a decisive role in the cancer immunity cycle. Indeed, endogenous PRR activation within the tumor microenvironment (TME) has been shown to generate spontaneous antitumor T cell immunity, e.g., cGAS-STING mediated activation of antigen presenting cells after release of DNA from dying tumor cells. Thus, instigating intratumor PRR activation, particularly with the goal of generating Th1-promoting inflammation that stokes endogenous priming of antitumor CD8+ T cells, is a growing area of clinical investigation. This approach is analogous to in situ vaccination, ultimately providing a personalized antitumor response against relevant tumor associated antigens. Here I discuss clinical stage intratumor modalities that function via activation of PRRs. These approaches are being tested in various solid tumor contexts including melanoma, colorectal cancer, glioblastoma, head and neck squamous cell carcinoma, bladder cancer, and pancreatic cancer. Their mechanism (s) of action relative to other immunotherapy approaches (e.g., antigen-defined cancer vaccines, CAR T cells, dendritic cell vaccines, and immune checkpoint blockade), as well as their potential to complement these approaches are also discussed. Examples to be reviewed include TLR agonists, STING agonists, RIG-I agonists, and attenuated or engineered viruses and bacterium. I also review common key requirements for effective in situ immune activation, discuss differences between various strategies inclusive of mechanisms that may ultimately limit or preclude antitumor efficacy, and provide a summary of relevant clinical data.
Collapse
Affiliation(s)
- Michael Brown
- Department of Neurosurgery, Duke University, Durham, NC, USA.
| |
Collapse
|
|
34
|
Differential In Vitro Growth and Cell Killing of Cancer versus Benign Prostate Cells by Oncolytic Parainfluenza Virus. Pathogens 2022; 11:pathogens11050493. [PMID: 35631014 PMCID: PMC9147676 DOI: 10.3390/pathogens11050493] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 12/24/2022] Open
Abstract
The development of effective oncolytic viruses will require understanding the differences in virus replication and killing between normal and cancer cells. Here, we have evaluated infections of metastatic cancer (22Rv1) and benign non-tumorigenic (BPH-1) prostate cell lines with a mutant parainfluenza virus 5 (P/V/F) encoding a defective V protein and a hyperfusogenic F protein. Under low multiplicity of infection (MOI), the P/V/F mutant efficiently spread in 22Rv1 cells but was restricted in BPH-1 cells due to type-I interferon (IFN-I) responses. In mixed co-cultures, the P/V/F mutant showed specificity towards and spread within the 22Rv1 cells versus BPH-1 cells. Under high MOI conditions, both BPH-1 and 22Rv1 cells showed efficient infection by the P/V/F mutant. However, compared to BPH-1 cells, the 22Rv1 cancer cells showed increased cytopathic effect, higher induction of caspase-8 and -9, and extensive syncytia formation. In 22Rv1 spheroid cultures, P/V/F infection was less efficient compared to monolayers, but the virus was able to spread through spheroids and induce death. These data indicate that IFN-I sensitivity is a major determinant of specificity of P/V/F spread through populations of cancer versus benign cells, and additionally, differences in activation of apoptotic pathways and syncytia formation can contribute to differential outcomes in cancer versus benign cells.
Collapse
|
|
35
|
de Graaf J, van Nieuwkoop S, de Meulder D, Lexmond P, Kuiken T, Groeneveld D, Fouchier R, van den Hoogen B. Assessment of the virulence for chickens of Newcastle Disease virus with an engineered multi-basic cleavage site in the fusion protein and disrupted V protein gene. Vet Microbiol 2022; 269:109437. [DOI: 10.1016/j.vetmic.2022.109437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 10/18/2022]
|
|
36
|
Optimizing environmental safety and cell-killing potential of oncolytic Newcastle Disease virus with modifications of the V, F and HN genes. PLoS One 2022; 17:e0263707. [PMID: 35139115 PMCID: PMC8827430 DOI: 10.1371/journal.pone.0263707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 01/26/2022] [Indexed: 11/19/2022] Open
Abstract
Newcastle Disease Virus (NDV) is an avian RNA virus, which was shown to be effective and safe for use in oncolytic viral therapy for several tumour malignancies. The presence of a multi basic cleavage site (MBCS) in the fusion protein improved its oncolytic efficacy in vitro and in vivo. However, NDV with a MBCS can be virulent in poultry. We aimed to develop an NDV with a MBCS but with reduced virulence for poultry while remaining effective in killing human tumour cells. To this end, the open reading frame of the V protein, an avian specific type I interferon antagonist, was disrupted by introducing multiple mutations. NDV with a mutated V gene was attenuated in avian cells and chicken and duck eggs. Although this virus still killed tumour cells, the efficacy was reduced compared to the virulent NDV. Introduction of various mutations in the fusion (F) and hemagglutinin-neuraminidase (HN) genes slightly improved this efficacy. Taken together, these data demonstrated that NDV with a MBCS but with abrogation of the V protein ORF and mutations in the F and HN genes can be safe for evaluation in oncolytic viral therapy.
Collapse
|
|
37
|
Carter ME, Koch A, Lauer UM, Hartkopf AD. Clinical Trials of Oncolytic Viruses in Breast Cancer. Front Oncol 2021; 11:803050. [PMID: 35004328 PMCID: PMC8733599 DOI: 10.3389/fonc.2021.803050] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/06/2021] [Indexed: 12/21/2022] Open
Abstract
Breast cancer is the second most common kind of cancer worldwide and oncolytic viruses may offer a new treatment approach. There are three different types of oncolytic viruses used in clinical trials; (i) oncolytic viruses with natural anti-neoplastic properties; (ii) oncolytic viruses designed for tumor-selective replication; (iii) oncolytic viruses modified to activate the immune system. Currently, fourteen different oncolytic viruses have been investigated in eighteen published clinical trials. These trials demonstrate that oncolytic viruses are well tolerated and safe for use in patients and display clinical activity. However, these trials mainly studied a small number of patients with different advanced tumors including some with breast cancer. Future trials should focus on breast cancer and investigate optimal routes of administration, occurrence of neutralizing antibodies, viral gene expression, combinations with other antineoplastic therapies, and identify subtypes that are particularly suitable for oncolytic virotherapy.
Collapse
Affiliation(s)
- Mary E Carter
- Department of Obstetrics and Gynaecology, University of Tuebingen, Tuebingen, Germany
| | - André Koch
- Department of Obstetrics and Gynaecology, University of Tuebingen, Tuebingen, Germany
| | - Ulrich M Lauer
- Department of Internal Medicine VIII, Medical Oncology & Pneumology, University of Tuebingen, Tuebingen, Germany
| | - Andreas D Hartkopf
- Department of Obstetrics and Gynaecology, University of Tuebingen, Tuebingen, Germany
| |
Collapse
|
|
38
|
Yang L, Gu X, Yu J, Ge S, Fan X. Oncolytic Virotherapy: From Bench to Bedside. Front Cell Dev Biol 2021; 9:790150. [PMID: 34901031 PMCID: PMC8662562 DOI: 10.3389/fcell.2021.790150] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/12/2021] [Indexed: 01/23/2023] Open
Abstract
Oncolytic viruses are naturally occurring or genetically engineered viruses that can replicate preferentially in tumor cells and inhibit tumor growth. These viruses have been considered an effective anticancer strategy in recent years. They mainly function by direct oncolysis, inducing an anticancer immune response and expressing exogenous effector genes. Their multifunctional characteristics indicate good application prospects as cancer therapeutics, especially in combination with other therapies, such as radiotherapy, chemotherapy and immunotherapy. Therefore, it is necessary to comprehensively understand the utility of oncolytic viruses in cancer therapeutics. Here, we review the characteristics, antitumor mechanisms, clinical applications, deficiencies and associated solutions, and future prospects of oncolytic viruses.
Collapse
Affiliation(s)
- Ludi Yang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Xiang Gu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jie Yu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| |
Collapse
|
|
39
|
Warner BM, Santry LA, Leacy A, Chan M, Pham PH, Vendramelli R, Pei Y, Tailor N, Valcourt E, Leung A, He S, Griffin BD, Audet J, Willman M, Tierney K, Albietz A, Frost KL, Yates JG, Mould RC, Chan L, Mehrani Y, Knapp JP, Minott JA, Banadyga L, Safronetz D, Wood H, Booth S, Major PP, Bridle BW, Susta L, Kobasa D, Wootton SK. Intranasal vaccination with a Newcastle disease virus-vectored vaccine protects hamsters from SARS-CoV-2 infection and disease. iScience 2021; 24:103219. [PMID: 34632328 PMCID: PMC8492382 DOI: 10.1016/j.isci.2021.103219] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/24/2021] [Accepted: 09/30/2021] [Indexed: 02/08/2023] Open
Abstract
The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Worldwide efforts are being made to develop vaccines to mitigate this pandemic. We engineered two recombinant Newcastle disease virus (NDV) vectors expressing either the full-length SARS-CoV-2 spike protein (NDV-FLS) or a version with a 19 amino acid deletion at the carboxy terminus (NDV-Δ19S). Hamsters receiving two doses (prime-boost) of NDV-FLS developed a robust SARS-CoV-2-neutralizing antibody response, with elimination of infectious virus in the lungs and minimal lung pathology at five days post-challenge. Single-dose vaccination with NDV-FLS significantly reduced SARS-CoV-2 replication in the lungs but only mildly decreased lung inflammation. NDV-Δ19S-treated hamsters had a moderate decrease in SARS-CoV-2 titers in lungs and presented with severe microscopic lesions, suggesting that truncation of the spike protein was a less effective strategy. In summary, NDV-vectored vaccines represent a viable option for protection against COVID-19.
Collapse
Affiliation(s)
- Bryce M. Warner
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Lisa A. Santry
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Alexander Leacy
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Mable Chan
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Phuc H. Pham
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Robert Vendramelli
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Yanlong Pei
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Nikesh Tailor
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Emelissa Valcourt
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Anders Leung
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Shihua He
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Bryan D. Griffin
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Jonathan Audet
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Marnie Willman
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Kevin Tierney
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Alixandra Albietz
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Kathy L. Frost
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Jacob G.E. Yates
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Robert C. Mould
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Lily Chan
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Yeganeh Mehrani
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Jason P. Knapp
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | | | - Logan Banadyga
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - David Safronetz
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Heidi Wood
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Stephanie Booth
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
| | - Pierre P. Major
- Juravinski Cancer Centre, 699 Concession Street, Hamilton, ON L8V 5C2, Canada
| | - Byram W. Bridle
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Leonardo Susta
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Darwyn Kobasa
- Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Sarah K. Wootton
- Department of Pathobiology, University of Guelph, Guelph, Canada
| |
Collapse
|
|
40
|
Uchihashi T, Nakahara H, Fukuhara H, Iwai M, Ito H, Sugauchi A, Tanaka M, Kogo M, Todo T. Oncolytic herpes virus G47Δ injected into tongue cancer swiftly traffics in lymphatics and suppresses metastasis. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:388-398. [PMID: 34553027 PMCID: PMC8430046 DOI: 10.1016/j.omto.2021.06.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/09/2021] [Indexed: 01/02/2023]
Abstract
The prognosis of oral squamous cell carcinoma (OSCC) largely depends on the control of lymph node metastases. We evaluate the therapeutic efficacy of G47Δ, a third-generation oncolytic herpes simplex virus type 1 (HSV-1), in mouse tongue cancer models. Intratumoral injection with G47Δ prolonged the survival in all orthotopic models investigated. In both athymic and immunocompetent models, G47Δ injected into the tongue cancer swiftly traffics to the draining cervical lymph nodes and suppresses lymph node metastases. In the immunocompetent KLN205-MUC1 model, in which the metastatic cascade that tongue cancer patients commonly experience is reproduced, intratumoral G47Δ injection even immediately prior to a tumor resection prolonged survival. Cervical lymph nodes 18 h after G47Δ treatment showed the presence of G47Δ infection and an increase in CD69-positive cells, indicating an immediate activation of T cells. Furthermore, G47Δ injected directly into enlarged metastatic lymph nodes significantly prolonged the survival at an advanced stage. Whereas intratumorally injected oncolytic HSV-1 does not readily circulate in the blood stream, G47Δ is shown to traffic in the lymphatics swiftly. The use of G47Δ can lead to entirely new treatment strategies for tongue cancer and other OSCC at all clinical stages.
Collapse
Affiliation(s)
- Toshihiro Uchihashi
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,The First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka, Japan
| | - Hirokazu Nakahara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hiroshi Fukuhara
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Miwako Iwai
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hirotaka Ito
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akinari Sugauchi
- The First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka, Japan
| | - Minoru Tanaka
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mikihiko Kogo
- The First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka, Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
41
|
Immunogenicity and protective efficacy of an intranasal live-attenuated vaccine against SARS-CoV-2. iScience 2021; 24:102941. [PMID: 34368648 PMCID: PMC8332743 DOI: 10.1016/j.isci.2021.102941] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 06/27/2021] [Accepted: 07/30/2021] [Indexed: 01/08/2023] Open
Abstract
Global deployment of an effective and safe vaccine is necessary to curtail the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we evaluated a Newcastle disease virus (NDV)-based vectored-vaccine in mice and hamsters for its immunogenicity, safety, and protective efficacy against SARS-CoV-2. Intranasal administration of recombinant (r)NDV-S vaccine expressing spike (S) protein of SARS-CoV-2 to mice induced high levels of SARS-CoV-2-specific neutralizing immunoglobulin A (IgA) and IgG2a antibodies and T-cell-mediated immunity. Hamsters immunized with two doses of vaccine showed complete protection from lung infection, inflammation, and pathological lesions following SARS-CoV-2 challenge. Importantly, administration of two doses of intranasal rNDV-S vaccine significantly reduced the SARS-CoV-2 shedding in nasal turbinate and lungs in hamsters. Collectively, intranasal vaccination has the potential to control infection at the site of inoculation, which should prevent both clinical disease and virus transmission to halt the spread of the COVID-19 pandemic.
Vaccine induces high levels of neutralizing Abs and T-cell-mediated immunity Vaccine ameliorates lung inflammation and pathology in hamster induced by SARS-CoV-2 The SARS-CoV-2 remains undetectable in lungs and nasal turbinates of vaccinated hamster Two doses of intranasal vaccine show complete protection against SARS-CoV-2 challenge
Collapse
|
|
42
|
Malogolovkin A, Gasanov N, Egorov A, Weener M, Ivanov R, Karabelsky A. Combinatorial Approaches for Cancer Treatment Using Oncolytic Viruses: Projecting the Perspectives through Clinical Trials Outcomes. Viruses 2021; 13:1271. [PMID: 34209981 PMCID: PMC8309967 DOI: 10.3390/v13071271] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/21/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023] Open
Abstract
Recent cancer immunotherapy breakthroughs have fundamentally changed oncology and revived the fading hope for a cancer cure. The immune checkpoint inhibitors (ICI) became an indispensable tool for the treatment of many malignant tumors. Alongside ICI, the application of oncolytic viruses in clinical trials is demonstrating encouraging outcomes. Dozens of combinations of oncolytic viruses with conventional radiotherapy and chemotherapy are widely used or studied, but it seems quite complicated to highlight the most effective combinations. Our review summarizes the results of clinical trials evaluating oncolytic viruses with or without genetic alterations in combination with immune checkpoint blockade, cytokines, antigens and other oncolytic viruses as well. This review is focused on the efficacy and safety of virotherapy and the most promising combinations based on the published clinical data, rather than presenting all oncolytic virus variations, which are discussed in comprehensive literature reviews. We briefly revise the research landscape of oncolytic viruses and discuss future perspectives in virus immunotherapy, in order to provide an insight for novel strategies of cancer treatment.
Collapse
Affiliation(s)
- Alexander Malogolovkin
- Gene Therapy Department, Sirius University of Science and Technology, Olympic Avenue, 1, 354340 Sochi, Russia; (N.G.); (A.E.); (M.W.); (R.I.)
| | | | | | | | | | - Alexander Karabelsky
- Gene Therapy Department, Sirius University of Science and Technology, Olympic Avenue, 1, 354340 Sochi, Russia; (N.G.); (A.E.); (M.W.); (R.I.)
| |
Collapse
|
|
43
|
Chen Y, Zhu S, Pei Y, Hu J, Hu Z, Liu X, Wang X, Gu M, Hu S, Liu X. Differential microRNA Expression in Newcastle Disease Virus-Infected HeLa Cells and Its Role in Regulating Virus Replication. Front Oncol 2021; 11:616809. [PMID: 34150610 PMCID: PMC8211993 DOI: 10.3389/fonc.2021.616809] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
As an oncolytic virus, Newcastle disease virus (NDV) can specifically kill tumor cells and has been tested as an attractive oncolytic agent for cancer virotherapy. Virus infection can trigger the changes of the cellular microRNA (miRNA) expression profile, which can greatly influence viral replication and pathogenesis. However, the interplay between NDV replication and cellular miRNA expression in tumor cells is still largely unknown. In the present study, we compared the profiles of cellular miRNAs in uninfected and NDV-infected HeLa cells by small RNA deep sequencing. Here we report that NDV infection in HeLa cells significantly changed the levels of 40 miRNAs at 6 h post-infection (hpi) and 62 miRNAs at 12 hpi. Among 23 highly differentially expressed miRNAs, NDV infection greatly promoted the levels of 3 miRNAs and suppressed the levels of 20 miRNAs at both time points. These 23 miRNAs are predicted to target various genes involved in virus replication and antiviral immunity such as ErbB, Jak-STAT, NF-kB and RIG-I-like receptor. Verification of deep sequencing results by quantitative RT-PCR showed that 9 out of 10 randomly selected miRNAs chosen from this 23-miRNA pool were consistent with deep sequencing data, including 6 down-regulated and 3 up-regulated. Further functional research revealed that hsa-miR-4521, a constituent in this 23-miRNA pool, inhibited NDV replication in HeLa cells. Moreover, dual-luciferase and gene expression array uncovered that the member A of family with sequence similarity 129 (FAM129A) was directly targeted by hsa-miR-4521 and positively regulated NDV replication in HeLa cells, indicating that hsa-miR-4521 may regulate NDV replication via interaction with FAM129A. To our knowledge, this is the first report of the dynamic cellular miRNA expression profile in tumor cells after NDV infection and may provide a valuable basis for further investigation on the roles of miRNAs in NDV-mediated oncolysis.
Collapse
Affiliation(s)
- Yu Chen
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Shanshan Zhu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Yuru Pei
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Jiao Hu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China
| | - Zenglei Hu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Xiaowen Liu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China
| | - Xiaoquan Wang
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Min Gu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China
| | - Shunlin Hu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Xiufan Liu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China
| |
Collapse
|
|
44
|
Mozaffari Nejad AS, Noor T, Munim ZH, Alikhani MY, Ghaemi A. A bibliometric review of oncolytic virus research as a novel approach for cancer therapy. Virol J 2021; 18:98. [PMID: 33980264 PMCID: PMC8113799 DOI: 10.1186/s12985-021-01571-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Background In recent years, oncolytic viruses (OVs) have drawn attention as a novel therapy to various types of cancers, both in clinical and preclinical cancer studies all around the world. Consequently, researchers have been actively working on enhancing cancer therapy since the early twentieth century. This study presents a systematic review of the literature on OVs, discusses underlying research clusters and, presents future directions of OVs research. Methods A total of 1626 published articles related to OVs as cancer therapy were obtained from the Web of Science (WoS) database published between January 2000 and March 2020. Various aspects of OVs research, including the countries/territories, institutions, journals, authors, citations, research areas, and content analysis to find trending and emerging topics, were analysed using the bibliometrix package in the R-software. Results In terms of the number of publications, the USA based researchers were the most productive (n = 611) followed by Chinese (n = 197), and Canadian (n = 153) researchers. The Molecular Therapy journal ranked first both in terms of the number of publications (n = 133) and local citations (n = 1384). The most prominent institution was Mayo Clinic from the USA (n = 117) followed by the University of Ottawa from Canada (n = 72), and the University of Helsinki from Finland (n = 63). The most impactful author was Bell J.C with the highest number of articles (n = 67) and total local citations (n = 885). The most impactful article was published in the Cell journal. In addition, the latest OVs research mainly builds on four research clusters. Conclusion The domain of OVs research has increased at a rapid rate from 2000 to 2020. Based on the synthesis of reviewed studies, adenovirus, herpes simplex virus, reovirus, and Newcastle disease virus have shown potent anti-cancer activity. Developed countries such as the USA, Canada, the UK, and Finland were the most productive, hence, contributed most to this field. Further collaboration will help improve the clinical research translation of this therapy and bring benefits to cancer patients worldwide.
Collapse
Affiliation(s)
| | - Tehjeeb Noor
- Faculty of Medicine, University of Bergen, Horten, Norway
| | - Ziaul Haque Munim
- Faculty of Technology, Natural and Maritime Sciences, University of South-Eastern Norway, Horten, Norway
| | - Mohammad Yousef Alikhani
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Amir Ghaemi
- Department of Influenza and Other Respiratory Viruses, Pasteur Institute of Iran, Tehran, Iran.
| |
Collapse
|
|
45
|
Jin KT, Du WL, Liu YY, Lan HR, Si JX, Mou XZ. Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements. Cancers (Basel) 2021; 13:cancers13040588. [PMID: 33546172 PMCID: PMC7913179 DOI: 10.3390/cancers13040588] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/26/2021] [Accepted: 01/30/2021] [Indexed: 12/14/2022] Open
Abstract
Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.
Collapse
Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China; (K.-T.J.); (Y.-Y.L.)
| | - Wen-Lin Du
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China;
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Yu-Yao Liu
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China; (K.-T.J.); (Y.-Y.L.)
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China;
| | - Jing-Xing Si
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Correspondence: (J.-X.S.); (X.-Z.M.); Tel./Fax: +86-571-85893781 (J.-X.S.); +86-571-85893985 (X.-Z.M.)
| | - Xiao-Zhou Mou
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Correspondence: (J.-X.S.); (X.-Z.M.); Tel./Fax: +86-571-85893781 (J.-X.S.); +86-571-85893985 (X.-Z.M.)
| |
Collapse
|
|
46
|
Cuoco JA, Rogers CM, Mittal S. The oncolytic Newcastle disease virus as an effective immunotherapeutic strategy against glioblastoma. Neurosurg Focus 2021; 50:E8. [PMID: 33524945 DOI: 10.3171/2020.11.focus20842] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 11/16/2020] [Indexed: 11/06/2022]
Abstract
Glioblastoma is the most frequent primary brain tumor in adults, with a dismal prognosis despite aggressive resection, chemotherapeutics, and radiotherapy. Although understanding of the molecular pathogenesis of glioblastoma has progressed in recent years, therapeutic options have failed to significantly change overall survival or progression-free survival. Thus, researchers have begun to explore immunomodulation as a potential strategy to improve clinical outcomes. The application of oncolytic virotherapy as a novel biological to target pathogenic signaling in glioblastoma has brought new hope to the field of neuro-oncology. This class of immunotherapeutics combines selective cancer cell lysis prompted by virus induction while promoting a strong inflammatory antitumor response, thereby acting as an effective in situ tumor vaccine. Several investigators have reported the efficacy of experimental oncolytic viruses as demonstrated by improved long-term survival in cancer patients with advanced disease. Newcastle disease virus (NDV) is one of the most well-researched oncolytic viruses known to affect a multitude of human cancers, including glioblastoma. Preclinical in vitro and in vivo studies as well as human clinical trials have demonstrated that NDV exhibits oncolytic activity against glioblastoma, providing a promising avenue of potential treatment. Herein, the authors provide a detailed discussion on NDV as a mode of therapy for glioblastoma. They discuss the potential therapeutic pathways associated with NDV as demonstrated by in vitro and in vivo experiments as well as results from human trials. Moreover, they discuss current challenges, potential solutions, and future perspectives in utilizing NDV in the treatment of glioblastoma.
Collapse
Affiliation(s)
- Joshua A Cuoco
- 1Carilion Clinic Neurosurgery, Roanoke.,2Fralin Biomedical Research Institute at Virginia Tech Carilion School of Medicine, Roanoke.,3School of Neuroscience, Virginia Tech, Blacksburg; and
| | - Cara M Rogers
- 1Carilion Clinic Neurosurgery, Roanoke.,2Fralin Biomedical Research Institute at Virginia Tech Carilion School of Medicine, Roanoke.,3School of Neuroscience, Virginia Tech, Blacksburg; and
| | - Sandeep Mittal
- 1Carilion Clinic Neurosurgery, Roanoke.,2Fralin Biomedical Research Institute at Virginia Tech Carilion School of Medicine, Roanoke.,3School of Neuroscience, Virginia Tech, Blacksburg; and.,4Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, Virginia
| |
Collapse
|
|
47
|
Meng Q, He J, Zhong L, Zhao Y. Advances in the Study of Antitumour Immunotherapy for Newcastle Disease Virus. Int J Med Sci 2021; 18:2294-2302. [PMID: 33967605 PMCID: PMC8100649 DOI: 10.7150/ijms.59185] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/21/2021] [Indexed: 01/08/2023] Open
Abstract
This article reviews the preclinical research, clinical application and development of Newcastle disease virus (NDV) in the field of cancer therapy. Based on the distinctive antitumour properties of NDV and its positive interaction with the patient's immune system, this biologic could be considered a major breakthrough in cancer treatment. On one hand, NDV infection creates an inflammatory environment in the tumour microenvironment, which can directly activate NK cells, monocytes, macrophages and dendritic cells and promote the recruitment of immune cells. On the other hand, NDV can induce the upregulation of immune checkpoint molecules, which may break immune tolerance and immune checkpoint blockade resistance. In fact, clinical data have shown that NDV combined with immune checkpoint blockade can effectively enhance the antitumour response, leading to the regression of local tumours and distant tumours when injected, and this effect is further enhanced by targeted manipulation and modification of the NDV genome. At present, recombinant NDV and recombinant NDV combined with immune checkpoint blockers have entered different stages of clinical trials. Based on these studies, further research on NDV is warranted.
Collapse
Affiliation(s)
- Qiuxing Meng
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, China
| | - Jian He
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, China
| | - Liping Zhong
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, China
| | - Yongxiang Zhao
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, China
| |
Collapse
|
|
48
|
Sun W, Leist SR, McCroskery S, Liu Y, Slamanig S, Oliva J, Amanat F, Schäfer A, Dinnon KH, García-Sastre A, Krammer F, Baric RS, Palese P. Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as a live virus vaccine candidate. EBioMedicine 2020; 62:103132. [PMID: 33232870 PMCID: PMC7679520 DOI: 10.1016/j.ebiom.2020.103132] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Due to the lack of protective immunity of humans towards the newly emerged SARS-CoV-2, this virus has caused a massive pandemic across the world resulting in hundreds of thousands of deaths. Thus, a vaccine is urgently needed to contain the spread of the virus. METHODS Here, we describe Newcastle disease virus (NDV) vector vaccines expressing the spike protein of SARS-CoV-2 in its wild type format or a membrane-anchored format lacking the polybasic cleavage site. All described NDV vector vaccines grow to high titers in embryonated chicken eggs. In a proof of principle mouse study, the immunogenicity and protective efficacy of these NDV-based vaccines were investigated. FINDINGS We report that the NDV vector vaccines elicit high levels of antibodies that are neutralizing when the vaccine is given intramuscularly in mice. Importantly, these COVID-19 vaccine candidates protect mice from a mouse-adapted SARS-CoV-2 challenge with no detectable viral titer and viral antigen in the lungs. INTERPRETATION The results suggested that the NDV vector expressing either the wild type S or membrane-anchored S without the polybasic cleavage site could be used as live vector vaccine against SARS-CoV-2. FUNDING This work is supported by an NIAID funded Center of Excellence for Influenza Research and Surveillance (CEIRS) contract, the Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract, philanthropic donations and NIH grants.
Collapse
Affiliation(s)
- Weina Sun
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Sarah R Leist
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Stephen McCroskery
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Yonghong Liu
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Stefan Slamanig
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Justine Oliva
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Fatima Amanat
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Alexandra Schäfer
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Kenneth H Dinnon
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Florian Krammer
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Ralph S Baric
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Peter Palese
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
| |
Collapse
|
|
49
|
Burman B, Pesci G, Zamarin D. Newcastle Disease Virus at the Forefront of Cancer Immunotherapy. Cancers (Basel) 2020; 12:cancers12123552. [PMID: 33260685 PMCID: PMC7761210 DOI: 10.3390/cancers12123552] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/23/2022] Open
Abstract
Preclinical and clinical studies dating back to the 1950s have demonstrated that Newcastle disease virus (NDV) has oncolytic properties and can potently stimulate antitumor immune responses. NDV selectively infects, replicates within, and lyses cancer cells by exploiting defective antiviral defenses in cancer cells. Inflammation within the tumor microenvironment in response to NDV leads to the recruitment of innate and adaptive immune effector cells, presentation of tumor antigens, and induction of immune checkpoints. In animal models, intratumoral injection of NDV results in T cell infiltration of both local and distant non-injected tumors, demonstrating the potential of NDV to activate systemic adaptive antitumor immunity. The combination of intratumoral NDV with systemic immune checkpoint blockade leads to regression of both injected and distant tumors, an effect further potentiated by introduction of immunomodulatory transgenes into the viral genome. Clinical trials with naturally occurring NDV administered intravenously demonstrated durable responses across numerous cancer types. Based on these studies, further exploration of NDV is warranted, and clinical studies using recombinant NDV in combination with immune checkpoint blockade have been initiated.
Collapse
Affiliation(s)
- Bharat Burman
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (B.B.); (G.P.)
- Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Giulio Pesci
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (B.B.); (G.P.)
- Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Dmitriy Zamarin
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (B.B.); (G.P.)
- Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Department of Medicine, Weill-Cornell Medical College, New York, NY 10065, USA
- Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Correspondence:
| |
Collapse
|
|
50
|
Cook M, Chauhan A. Clinical Application of Oncolytic Viruses: A Systematic Review. Int J Mol Sci 2020; 21:ijms21207505. [PMID: 33053757 PMCID: PMC7589713 DOI: 10.3390/ijms21207505] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023] Open
Abstract
Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic viruses. Trials were reviewed for type of oncolytic virus used, method of administration, study design, disease type, primary outcome, and relevant adverse effects. A total of 120 trials were found; 86 trials were available for our review. Included were 60 phase I trials, five phase I/II combination trials, 19 phase II trials, and two phase III clinical trials. Oncolytic viruses are feverously being evaluated in oncology with over 30 different types of oncolytic viruses being explored either as a single agent or in combination with other antitumor agents. To date, only one oncolytic virus therapy has received an FDA approval but advances in bioengineering techniques and our understanding of immunomodulation to heighten oncolytic virus replication and improve tumor kill raises optimism for its future drug development.
Collapse
Affiliation(s)
- Mary Cook
- Department of Internal Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, 22 S. Greene Street, Baltimore, MD 21201, USA;
| | - Aman Chauhan
- Department of Internal Medicine-Medical Oncology, University of Kentucky, Lexington, KY 40536, USA
- Markey Cancer Center, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA
- Correspondence: ; Tel.: +504-278-0134
| |
Collapse
|