A recent phase 3 clinical trial demonstrated that intravesical interferon-alpha (IFNα) gene therapy plus nadofaragene firadenovec is a clinically effective treatment combination for patients with non-muscle-invasive bladder cancer (NMIBC), providing a potential new therapeutic approach for a disease with a significant unmet clinical need.
Researchers from MD Anderson Cancer Center in Houston, Texas, have investigated the impact of IFNα gene therapy on tumor metabolism in a group of test mice, using in vitro and orthotopic preclinical models and trial data to uncover mechanisms of tumor resistance and identify predictive biomarkers.
Whole-transcriptome sequencing, glucose uptake, and lactate production were measured to analyze in vitro mice bladder cancer cell lines treated with recombinant IFNα and lentiviral IFNα (LV-IFNα). Preclinical bladder cancer models were treated with LV-IFNα (orthotopic tumor model) or poly (I:C) (flank tumor model), an IFN inducer.
In vivo real-time luciferase imaging was used to monitor disease response. Whole-transcriptome sequencing was performed to assess harvested tumors for the effects of IFNα therapy on metabolism and lipidomics. Lipidomic profiling was performed on patients’ urine samples from a separate phase 2 clinical trial that analyzed intravesical nadofaragene firadenovec (7 clinical responders and 6 nonresponders) for clinically relevant differences in lipid metabolism.
After using IFNα therapy in in vitro mice orthotopic bladder cancer models, the downregulation of genes involved in fatty acid synthesis was identified, as was the upregulation of genes involved in glycolysis by whole-transcriptome sequencing. A higher glucose uptake and lactate production by IFNα-treated cells in vitro confirmed these findings. The results were repeated in whole-transcriptome data sequencing of human bladder tumors that were treated with intravesical nadofaragene firadenovec.
Lipidomics that were performed on MB49 tumors in mice treated with poly (I:C) found 79 upregulated lipids, including phosphatidylcholine, sphingomyelin, and phosphatidyl ethanolamine, as well as 12 downregulated lipids, mainly from the cardiolipin class.
Lipidomics that were performed on patient urine samples collected before and after treatment with intravesical nadofaragene firadenovec found more than 592 lipids with distinct expression profiles differentiating clinical responders and nonresponders at both time points.
Metabolic changes were found to be reproducible across in vitro, in vivo, and clinical trial studies to improve the mechanistic understanding of IFNα gene therapy, identify tumor escape pathways that can be targeted with combination therapy regimens, and identify new biomarkers to predict the clinical response of NMIBC to IFNα gene therapy.