Lentiviral interferon: A novel method for gene therapy in bladder cancer

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, Burles A. Johnson, Bogdan A. Czerniak, Tiina Nieminen, Tommi Heikura, Seppo Yla-Herttuala, Nigel R. Parker, Kimberley S. Schluns, David J. McConkeyColin P. Dinney

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)141-157
Number of pages17
JournalMolecular Therapy Oncolytics
Volume26
DOIs
StatePublished - Sep 15 2022

Keywords

  • IL-6
  • MB49
  • bladder cancer
  • gene therapy
  • interferon alpha
  • intravesical
  • lentiviral vector

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Molecular Medicine
  • Oncology
  • Cancer Research

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