A Multicenter Pilot Study of MUC1 Vaccine in Current and Former Smokers at High Risk for Lung Cancer.

Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. Mucin (MUC)1 glycoprotein is aberrantly expressed in lung carcinomas and premalignant lung lesions. We explored whether a MUC1 vaccine might be effective in halting neoplastic development and progression in individuals at high risk for lung cancer.

Methods: We conducted a multicenter trial of a MUC1 vaccine in current and former heavy smokers to evaluate immunogenicity and safety. Smoking history of ≥30 pack-years and CT chest showing either no nodules or nodules < 6 mm were inclusion criteria. A vaccine containing MUC1 peptide was administered at weeks 0, 2 and 10. Blood was collected pre-vaccine administration, 2 weeks after each vaccine, and at week 24. Immunogenicity (primary endpoint) and the presence of myeloid-derived suppressor cells (MDSC) and regulatory T cells (secondary endpoints) were assessed. Adverse events and toxicities were monitored.

Results: Of 77 individuals screened, 50 were registered and 45 completed the study (27 current and 18 former smokers). The vaccine was well-tolerated. Four current (14.8%) and 2 former smokers (11.1%) developed anti-MUC1 IgG titers ≥2 fold higher at week 12 as compared with baseline, with an overall immune response rate of 13.3% (95% CI 5.1-26.8%). We found high circulating levels of immunosuppressive MDSCs in both current and former smokers.

Conclusions: Administering a potentially preventive vaccine is feasible and safe in individuals at high risk for lung cancer. However, this cohort exhibited a high level of immune suppression, previously documented only in patients with advanced lung cancer. Nonetheless, a vaccine-induced immune response was noted in 13% of participants. Further work is required to refine participant selection, understand the factors driving immunosuppression, and counteract these factors to apply immunoprevention strategies in this high-risk population.

Translational Relevance: Vaccines targeting antigens aberrantly expressed on lung cancers and their precursors offer the potential for a relatively non-invasive prevention strategy. Worldwide, lung cancer remains the most important cause of cancer-related mortality, and an immunoprevention approach, if successful, has the potential to save many lives by prevention of lung cancer. All epithelial tumors, including lung cancer, express high levels of abnormal mucin (MUC)1 and MUC1-based therapeutic vaccines can increase this immune response to aberrant expressed MUC1 to therapeutic levels.We conducted a multicenter trial to evaluate the immunogenicity and safety of a MUC1 preventive vaccine in individuals with a significant smoking history and at high risk of developing lung cancer. The MUC1 vaccine was safe and elicited an immune response in 13%, which was lower than anticipated. Unexpectedly, we observed a high level of immune suppression in this cohort of heavy smokers, which has been previously documented in individuals who already have lung cancer. Although immunoprevention strategies are promising for reducing the risk of lung cancer in current and former heavy smokers, the immune environment induced by smoking, and the factors that drive immunosuppression are crucial barriers that must be overcome by well-designed immunoprevention strategies for lung cancer.