Adjuvant Immunotherapy with Surgery Improves Survival in Murine Models of Thoracic Malignancies

Abstract

Abstract Objectives Immunotherapy is an alternative therapy for thoracic malignancies, but results in humans have not been as impressive as anticipated. We hypothesized that adjuvant immunotherapy with surgery debulking can improve efficacy and long term response rates. Methods We retrospectively reviewed our group’s experience with human immunotherapy trials for NSCLC and mesothelioma. We developed murine models of NSCLC and mesothelioma surgery to evaluate clinically applicable immunotherapy approaches (tumor vaccination and checkpoint inhibitors) and optimized regimen. Outcomes were assessed for overall survival and tumor progression. Flow Cytometry, ELISA, PCR and in vivo neutralization assays were utilized to determine immune responses. Results The most important predictor of immunotherapy response in human trials was minimal disease at the time of immunotherapy. Surgery generates a state of minimum disease, thus we used a murine cancer surgery model to evaluate clinically available adjuvant immunotherapy approaches in a controlled setting. Adjuvant vaccination strategies were associated with decreased tumor volumes (p<0.01) and were associated with an increase in postoperative survival (42 days vs 24 days, p=0.03). In vivo lymphocyte assays demonstrated only partial cytotoxic activity of CD8+ T-cells postoperatively. The addition of checkpoint inhibitor (CTLA4i) with tumor vaccination improved potency and nearly tripled post-operative survival (54 days vs 19 days; p=0.004). Additionally, 34% of mice receiving combination immunotherapy with surgery were cured (p=0.03). Conclusion This evidence supports a new approach to thoracic malignancies including multi modal immunotherapy with surgical resection.