Combination Treatment with Intravesical Interferon-Alpha Gene Therapy and an Oral Pan-Erbb Receptor Family Blocker Improves Survival in Mice with Bladder Cancer

IntroductionIntravesical interferon-alpha (IFNα) gene therapy is approved by the FDA for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Identifying resistance mechanisms and deploying targeted combination treatment strategies is a rational approach to improving treatment responses. We identified the ErbB pathway as a resistance mechanism to IFNα gene therapy, and we hypothesized that combination treatment with an ErbB pathway blocker and IFN-α could improve outcomes in resistant tumors.MethodsMurine bladder cancer cells were treated in vitro with lentiviral IFNα (LV-IFNα) gene therapy, with/without afatinib (Afa), a pan-ErbB inhibitor, and cell viability and migration assays were performed. In vivo studies were conducted in a syngeneic MB49 orthotopic murine bladder cancer model, and mice were randomized into five treatment groups and treated with single treatments: Ctrl (vehicle), LV-Ctrl, LV-IFNα, and combination treatments with LV-Ctrl/Afa or LV-IFNα/Afa.ResultsCombination therapy with LV-IFNα/Afa significantly reduced MB49 cell viability in vitro compared to all other treatment conditions. This additive effect on cell viability appeared to be driven by a combination of early-cytostatic and late-cytolytic effects. The combination treatment also markedly inhibited cell migration. Finally, the in vivo studies demonstrated improved overall survival (OS) with LV-IFNα/Afa (median OS was 49 days in the LV-IFNα/Afa group vs. 15, 14, 29, and 26 days in Ctrl, LV-Ctrl, LV-IFNα, and LV-Ctrl/Afa groups, respectively; log-rank p < 0.001).ConclusionOur findings suggest that the ErbB pathway may serve as a clinically actionable resistance mechanism to intravesical IFNα gene therapy and, when targeted concurrently, it may improve treatment efficacy.