Aerosolized Oncolytic Viral Therapy: A Targeted Approach for EGFR-Mutant Lung Cancer

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases.1 Among these, 40–80% exhibit mutations or overexpression of the epidermal growth factor receptor (EGFR), which has emerged as a key target for immunotherapies.2 Despite recent advancements, EGFR-mutant NSCLC continues to face poor prognosis, largely due to immune evasion and resistance to current treatments. To address this, we propose a novel, aerosolized oncolytic viral (OV) therapy, specifically designed to target EGFR-mutant NSCLC. Our approach utilizes measles virus as the vector, a well-characterized and respiratory-tropic virus with a strong clinical safety record.3 The OV will be delivered in an aerosolized form, enabling direct administration to lung tissue and maximizing viral deposition at tumor sites while minimizing systemic clearance. Our measles-based OV will specifically target EGFR-mutant cells and induce an immune response through three biological modifications. Accurate binding will be effectuated using modified affibody ligands, allowing targeted viral entry.4 Tumor-specific promoters such as Survivin, which is active in neoplastic cells, will be expressed by our OV.5 Upon recognition and viral entry, our aerosolized OV will express immunogenic genes, releasing molecules such as IL-12 to and granulocyte-macrophage colony-stimulating factor (GM-CSF) to trigger an immune response and ultimately immunogenic cell death (ICD).6 These mechanisms will leave surrounding healthy cells intact, while allowing a powerful, adaptive response to occur. Previous studies have utilized herpes simplex virus (HSV) vectors for OV therapy in EGFR-mutant NSCLC, successfully modifying them to target tumors using strategies comparable to ours.4 Though efficient oncolysis and the induction of antitumor immunity was achieved, delivery of OVs showed to be the largest issue, which our novel method addresses.4 Thus, our aerosolized OV therapy offers a non-invasive, targeted approach to EGFR-mutant NSCLC, with the potential to significantly improve patient outcomes.