Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models
Abstract Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high‐grade disease, Bacillus Calmette–Guérin (BCG), fails in 30% of patients. We have generated a n...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201607296 |
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| author | Kyle G Potts Chad R Irwin Nicole A Favis Desmond B Pink Krista M Vincent John D Lewis Ronald B Moore Mary M Hitt David H Evans |
| author_facet | Kyle G Potts Chad R Irwin Nicole A Favis Desmond B Pink Krista M Vincent John D Lewis Ronald B Moore Mary M Hitt David H Evans |
| author_sort | Kyle G Potts |
| collection | DOAJ |
| description | Abstract Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high‐grade disease, Bacillus Calmette–Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell‐cycle‐regulated small subunit of ribonucleotide reductase (RRM2). The F4L‐deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor‐selective replication and cell killing. These F4L‐deleted VACVs replicated selectively in immune‐competent rat AY‐27 and xenografted human RT112‐luc orthotopic bladder cancer models, causing significant tumor regression or complete ablation with no toxicity. It was also observed that rats cured of AY‐27 tumors by VACV treatment developed anti‐tumor immunity as evidenced by tumor rejection upon challenge and by ex vivo cytotoxic T‐lymphocyte assays. Finally, F4L‐deleted VACVs replicated in primary human bladder cancer explants. Our findings demonstrate the enhanced safety and selectivity of F4L‐deleted VACVs, with application as a promising therapy for patients with BCG‐refractory cancers and immune dysregulation. |
| format | Article |
| id | doaj-art-7a25d246a5d84cfdbca40ab0fd93b132 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-7a25d246a5d84cfdbca40ab0fd93b1322025-08-20T03:46:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-03-019563865410.15252/emmm.201607296Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer modelsKyle G Potts0Chad R Irwin1Nicole A Favis2Desmond B Pink3Krista M Vincent4John D Lewis5Ronald B Moore6Mary M Hitt7David H Evans8Department of Oncology, Faculty of Medicine and Dentistry, University of AlbertaLi Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of AlbertaLi Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of AlbertaDepartment of Oncology, Faculty of Medicine and Dentistry, University of AlbertaDepartment of Oncology, Faculty of Medicine and Dentistry, University of AlbertaDepartment of Oncology, Faculty of Medicine and Dentistry, University of AlbertaDepartment of Oncology, Faculty of Medicine and Dentistry, University of AlbertaDepartment of Oncology, Faculty of Medicine and Dentistry, University of AlbertaLi Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of AlbertaAbstract Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high‐grade disease, Bacillus Calmette–Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell‐cycle‐regulated small subunit of ribonucleotide reductase (RRM2). The F4L‐deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor‐selective replication and cell killing. These F4L‐deleted VACVs replicated selectively in immune‐competent rat AY‐27 and xenografted human RT112‐luc orthotopic bladder cancer models, causing significant tumor regression or complete ablation with no toxicity. It was also observed that rats cured of AY‐27 tumors by VACV treatment developed anti‐tumor immunity as evidenced by tumor rejection upon challenge and by ex vivo cytotoxic T‐lymphocyte assays. Finally, F4L‐deleted VACVs replicated in primary human bladder cancer explants. Our findings demonstrate the enhanced safety and selectivity of F4L‐deleted VACVs, with application as a promising therapy for patients with BCG‐refractory cancers and immune dysregulation.https://doi.org/10.15252/emmm.201607296bladder cancerimmunotherapyoncolytic virusribonucleotide reductasevaccinia virus |
| spellingShingle | Kyle G Potts Chad R Irwin Nicole A Favis Desmond B Pink Krista M Vincent John D Lewis Ronald B Moore Mary M Hitt David H Evans Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models EMBO Molecular Medicine bladder cancer immunotherapy oncolytic virus ribonucleotide reductase vaccinia virus |
| title | Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models |
| title_full | Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models |
| title_fullStr | Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models |
| title_full_unstemmed | Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models |
| title_short | Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models |
| title_sort | deletion of f4l ribonucleotide reductase in vaccinia virus produces a selective oncolytic virus and promotes anti tumor immunity with superior safety in bladder cancer models |
| topic | bladder cancer immunotherapy oncolytic virus ribonucleotide reductase vaccinia virus |
| url | https://doi.org/10.15252/emmm.201607296 |
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