Lentiviral interferon: A novel method for gene therapy in bladder cancer
Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient tran...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-09-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770522000833 |
| _version_ | 1811334807083286528 |
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| author | Sharada Mokkapati Vikram M. Narayan Ganiraju C. Manyam Amy H. Lim Jonathan J. Duplisea Andrea Kokorovic Tanner S. Miest Anirban P. Mitra Devin Plote Selvalakshmi Selvaraj Anand Michael J. Metcalfe Kenneth Dunner, Jr. Burles A. Johnson Bogdan A. Czerniak Tiina Nieminen Tommi Heikura Seppo Yla-Herttuala Nigel R. Parker Kimberley S. Schluns David J. McConkey Colin P. Dinney |
| author_facet | Sharada Mokkapati Vikram M. Narayan Ganiraju C. Manyam Amy H. Lim Jonathan J. Duplisea Andrea Kokorovic Tanner S. Miest Anirban P. Mitra Devin Plote Selvalakshmi Selvaraj Anand Michael J. Metcalfe Kenneth Dunner, Jr. Burles A. Johnson Bogdan A. Czerniak Tiina Nieminen Tommi Heikura Seppo Yla-Herttuala Nigel R. Parker Kimberley S. Schluns David J. McConkey Colin P. Dinney |
| author_sort | Sharada Mokkapati |
| collection | DOAJ |
| description | Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment. |
| first_indexed | 2024-04-13T17:14:34Z |
| format | Article |
| id | doaj.art-5de742af926648bcab7840c44c6fac3e |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-04-13T17:14:34Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-5de742af926648bcab7840c44c6fac3e2022-12-22T02:38:10ZengElsevierMolecular Therapy: Oncolytics2372-77052022-09-0126141157Lentiviral interferon: A novel method for gene therapy in bladder cancerSharada Mokkapati0Vikram M. Narayan1Ganiraju C. Manyam2Amy H. Lim3Jonathan J. Duplisea4Andrea Kokorovic5Tanner S. Miest6Anirban P. Mitra7Devin Plote8Selvalakshmi Selvaraj Anand9Michael J. Metcalfe10Kenneth Dunner, Jr.11Burles A. Johnson12Bogdan A. Czerniak13Tiina Nieminen14Tommi Heikura15Seppo Yla-Herttuala16Nigel R. Parker17Kimberley S. Schluns18David J. McConkey19Colin P. Dinney20University of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USA; Corresponding author Sharada Mokkapati, PhD, University of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USA.University of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAJames Buchanan Brady Urological Institute, John Hopkins Greenberg Bladder Cancer Institute, John Hopkins University, School of Medicine, Baltimore, MD, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandMiddlesex, Hamesman, Ltd., Edgware, London, UKUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USAJames Buchanan Brady Urological Institute, John Hopkins Greenberg Bladder Cancer Institute, John Hopkins University, School of Medicine, Baltimore, MD, USAUniversity of Texas MD Anderson Cancer Center, Smith Research Building, 7777 Knight Road, Houston, TX 77584, USA; Corresponding author Colin P. Dinney, MD, University of Texas MD Anderson Cancer Center, CPB7.3279, 1515 Holcombe Blvd., Houston, TX 77030, USA.Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.http://www.sciencedirect.com/science/article/pii/S2372770522000833interferon alphagene therapybladder cancerIL-6lentiviral vectorintravesical |
| spellingShingle | Sharada Mokkapati Vikram M. Narayan Ganiraju C. Manyam Amy H. Lim Jonathan J. Duplisea Andrea Kokorovic Tanner S. Miest Anirban P. Mitra Devin Plote Selvalakshmi Selvaraj Anand Michael J. Metcalfe Kenneth Dunner, Jr. Burles A. Johnson Bogdan A. Czerniak Tiina Nieminen Tommi Heikura Seppo Yla-Herttuala Nigel R. Parker Kimberley S. Schluns David J. McConkey Colin P. Dinney Lentiviral interferon: A novel method for gene therapy in bladder cancer Molecular Therapy: Oncolytics interferon alpha gene therapy bladder cancer IL-6 lentiviral vector intravesical |
| title | Lentiviral interferon: A novel method for gene therapy in bladder cancer |
| title_full | Lentiviral interferon: A novel method for gene therapy in bladder cancer |
| title_fullStr | Lentiviral interferon: A novel method for gene therapy in bladder cancer |
| title_full_unstemmed | Lentiviral interferon: A novel method for gene therapy in bladder cancer |
| title_short | Lentiviral interferon: A novel method for gene therapy in bladder cancer |
| title_sort | lentiviral interferon a novel method for gene therapy in bladder cancer |
| topic | interferon alpha gene therapy bladder cancer IL-6 lentiviral vector intravesical |
| url | http://www.sciencedirect.com/science/article/pii/S2372770522000833 |
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