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

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Mokkapati S, Narayan VM, Manyam GC, Lim AH, Duplisea JJ, Kokorovic A, Miest TS, Mitra AP, Plote D, Anand SS, Metcalfe MJ, Dunner K Jr, Johnson BA, Czerniak BA, Nieminen T, Heikura T, Yla-Herttuala S, Parker NR, Schluns KS, McConkey DJ, Dinney CP

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

Mol Ther Oncolytics. 2022 Jun 10;26:141-157. doi: 10.1016/j.omto.2022.06.005. eCollection 2022 Sep 15.

PubMed ID
35847448 [ View in PubMed
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Abstract

Interferon alpha (IFNalpha) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNalpha 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 IFNalpha (LV-IFNalpha) and demonstrate IFNalpha 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-IFNalpha, 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-IFNalpha/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-IFNalpha/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNalpha and the study of novel combination strategies with IFNalpha gene therapy for the BLCA treatment.

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