Bacillus Calmette‐Guérin (BCG) and Interferon (IFN) Gene Therapy for Combination Bladder Cancer Treatment: A Mathematical Model for Improved Efficacy and Tolerability

Abstract Intravesical instillation of Bacillus Calmette‐Guérin (BCG) bacteria represents the gold standard adjuvant therapy for non‐muscle‐invasive bladder cancer following tumor resection. Despite treatment efficacy, ≈50% of patients exhibit resistance to treatment or cannot complete the therapeutic course due to severe side effects. Nadofaragene firadenovec (IFN‐gene) therapy, recently FDA‐approved for BCG‐unresponsive patients, offers potential benefits by utilizing intravesical adenoviral infection to produce high local IFNα levels sustained for several days. By simulating changes in treatment protocols, mathematically, how combining these agents may provide more effective and better‐tolerated regimens for BCG non‐responder or intolerant patients is explored. Four equations are employed to model the dynamics of tumor cells, immune system responses, and BCG with IFN‐gene therapy interactions. The model predicts that improved outcomes, compared to basic protocols, can be achieved. Specifically, combining BCG and IFN‐gene therapy reduces the non‐responder rate from 52% to 32%. Moreover, reducing BCG dosage while combining it with IFN‐gene therapy in prolonged maintenance courses with five additional treatment cycles reduces non‐responders to 10%. IFN‐gene therapy creates stable windows of opportunity for enhanced immune system responses, achieving improved BCG‐stimulated malignant urothelial cell killing. The protocol assists future rational clinical trial planning to test these hypotheses.