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      Cell-derived Newcastle disease virus variant with two amino acid substitutions near cleavage site of F shows favorable traits as oncolytic virus

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          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.

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          Abstract

          van den Hoogen and colleagues show that introduction of V- 106-M and L- 117-S amino acid substitutions in NDV resulted in the ability to produce virus in mammalian cells without the use of embryonated chicken eggs. These substitutions enhanced viral replication and induced cell-killing in pancreatic cancer cell lines while remaining non-virulent.

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          Most cited references34

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          A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT ENDPOINTS12

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            Oncolytic viruses: a new class of immunotherapy drugs

            Key Points Oncolytic viruses mediate anti-tumour responses through a dual mechanism involving viral oncolysis of cancer cells and induction of host anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements, release of danger signals and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been utilized as oncolytic vectors in preclinical studies, which have demonstrated therapeutic activity against several types of cancer. Oncolytic viruses can be genetically modified to decrease pathogenicity, increase lytic potential and enhance immunogenicity, improving the risk–benefit ratio for clinical development. The approval of a modified adenovirus, H101, in China and the pending approval of a modified herpes simplex virus type 1 (HSV-1) encoding granulocyte–macrophage colony stimulating factor (GM-CSF), termed talimogene laherparepvec (T-VEC), by the US Food and Drug Administration (FDA) in the United States is likely to promote further drug development within this new class of cancer therapeutics. Oncolytic viruses face unique challenges in drug development, including the need for optimal clinical trial designs and response assessment that capture therapeutic responses, different regulatory and commercialization pathways, the need for live culture scale-up procedures, and novel biosafety concerns related to viral persistence in patients and transmission to household contacts and health-care providers. Supplementary information The online version of this article (doi:10.1038/nrd4663) contains supplementary material, which is available to authorized users.
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              Generation of bovine respiratory syncytial virus (BRSV) from cDNA: BRSV NS2 is not essential for virus replication in tissue culture, and the human RSV leader region acts as a functional BRSV genome promoter.

              In order to generate recombinant bovine respiratory syncytial virus (BRSV), the genome of BRSV strain A51908, variant ATue51908, was cloned as cDNA. We provide here the sequence of the BRSV genome ends and of the entire L gene. This completes the sequence of the BRSV genome, which comprises a total of 15,140 nucleotides. To establish a vaccinia virus-free recovery system, a BHK-derived cell line stably expressing T7 RNA polymerase was generated (BSR T7/5). Recombinant BRSV was reproducibly recovered from cDNA constructs after T7 RNA polymerase-driven expression of antigenome sense RNA and of BRSV N, P, M2, and L proteins from transfected plasmids. Chimeric viruses in which the BRSV leader region was replaced by the human respiratory syncytial virus (HRSV) leader region replicated in cell culture as efficiently as their nonchimeric counterparts, demonstrating that all cis-acting sequences of the HRSV promoter are faithfully recognized by the BRSV polymerase complex. In addition, we report the successful recovery of a BRSV mutant lacking the complete NS2 gene, which encodes a nonstructural protein of unknown function. The NS2-deficient BRSV replicated autonomously and could be passaged, demonstrating that NS2 is not essential for virus replication in cell culture. However, growth of the mutant was considerably slower than and final infectious titers were reduced by a factor of at least 10 compared to wild-type BRSV, indicating that NS2 provides a supporting factor required for full replication capacity.
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                Author and article information

                Contributors
                Journal
                Mol Ther Oncol
                Mol Ther Oncol
                Molecular Therapy Oncology
                American Society of Gene & Cell Therapy
                2950-3299
                06 December 2024
                20 March 2025
                06 December 2024
                : 33
                : 1
                : 200915
                Affiliations
                [1 ]Department of Viroscience, Erasmus Medical Centrum, Doctor Molewaterplein 40, 3015 CN Rotterdam, the Netherlands
                [2 ]Department of Immunology, Leids Universitair Medisch Centrum, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
                Author notes
                []Corresponding author: Bernadette G. van den Hoogen, Department of Viroscience, Erasmus Medical Centrum, Doctor Molewaterplein 40, 3015 CN Rotterdam, the Netherlands. b.vandenhoogen@ 123456erasmusmc.nl
                Article
                S2950-3299(24)00157-7 200915
                10.1016/j.omton.2024.200915
                11719830
                39802675
                d4bd8103-bfd4-45c3-9e17-07c483be139b
                © 2024 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 May 2024
                : 21 October 2024
                : 3 December 2024
                Categories
                Original Article

                mt: regular issue,newcastle disease virus,ndv,viro-immunotherapy,pancreatic cancer,embryonated chicken eggs,mammalian cells,human complement system,amino acid substitutions,cleavage site

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