A Phase I Dose-Escalation Clinical Trial of Bronchoscopic Cryoimmunotherapy in Advanced-Stage NSCLC.

Introduction: Outcomes for NSCLC remain suboptimal. Recent data suggest that cryoablation can generate antitumor immune effects. In this first-in-human phase I clinical trial, we investigated the safety and feasibility of bronchoscopic cryoimmunotherapy (BCI) delivered during standard-of-care bronchoscopy and explored associated systemic immune responses. Methods: Subjects with known or suspected advanced-stage NSCLC were recruited. BCI was delivered in dose-escalated freeze-thaw cycles to determine maximum dose tolerance. Feasibility assessment was determined with a pre-set goal of achieving successful BCI in more than or equal to 80% of subjects. Safety was assessed by review of BCI-related complications, including grades 2 to 3 bleeding, pneumothorax requiring intervention, and National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 to 5 adverse events. Pre- and post-BCI blood samples were collected to explore changes in the systemic immune profile. Results: Subjects with predominantly clinical TNM stage 3 or 4 adenocarcinoma or squamous cell carcinoma were enrolled. We reached the maximum dose of 30 seconds with 100% feasibility and no BCI-related adverse events. In peripheral blood analysis, we observed a significant decrease in derived neutrophil-to-lymphocyte ratio in the high-dose BCI group in comparison to the low-dose BCI cohort. We also observed increases in inflammatory cytokines-GM-CSF, IFN-γ, IL-1β, IL-17A, and IL-2-and effector memory T cells post-BCI. Conclusion: BCI is safe and feasible. In addition, we provide preliminary evidence that at higher dose levels there is a systemic immune response consistent with a cytotoxic profile. Further immune analyses will determine the potential of BCI as an adjunctive therapy in combination with immune checkpoint inhibition in NSCLC treatment.