Randomized phase II clinical trial of NY-ESO-1 protein vaccine combined with cholesteryl pullulan (CHP-NY-ESO-1) in resected esophageal cancer patients

Abstract

Background: Since PD‐1/PD‐L1 blockade has displayed clinical efficacy in esophageal cancer patients, an immunological therapeutic approach such as a cancer vaccine will be realistic in clinics. NY‐ESO‐1, one of cancer‐testis antigens, is expressed in approximately 30% esophageal squamous cell carcinoma (ESCC). Cholesteryl pullulan (CHP) is an antigen delivery system to antigen‐presenting cells including macrophages. The complex of CHP and NY‐ESO‐1 protein (CHP‐NY‐ESO‐1) is a vaccine that activates CD4+ and CD8+ T cells. We aimed to evaluate clinical efficacy of the CHP‐NY‐ESO‐1 for esophageal cancer patients after radical surgery in a randomized phase II trial. Methods: 54 NY‐ESO‐1‐expressing ESCC patients who underwent radical surgery following neoadjuvant chemotherapy of cisplatin/5‐FU were randomized to two arms, CHP‐NY‐ESO‐1 vaccine and observation as a control arm. The vaccine was composed of 200 mg full‐length NY‐ESO‐1 protein, which was subcutaneously given 15 doses with 2 or 4‐week interval for 12 months. Primary endpoints were disease‐free survival (DFS) and safety. Secondary endpoints were immune‐responses and overall survival (OS). 49 patients were evaluated for DFS and OS. Results: DFS in 2 years are 56.0% and 58.3% in the vaccine arm and in the control. OS in 2 years are 76.0% and 79.2%, respectively. No differences were seen between the vaccine and the control group. Subgroup analysis demonstrated that T‐bet+ CD8+ T cell infiltration was significantly correlated to DFS and that PD‐L1‐expression in tumors showed unfavorable tendency for the vaccine group. Exploratory analysis of intracohort correlations among the vaccinated patients revealed that 5% or more expression of NY‐ESO‐1 and high polymeric immunoglobulin receptor (PIGR)‐gene expression in tumors were favorable factors. Conclusions: The clinical trial revealed that CHP‐NY‐ESO‐1 vaccine alone did not display clinical efficacy compared to the control. It suggested that CHP‐NY‐ESO‐1 vaccine would be indicated to>5% NY‐ESO‐1 and/or high PIGR gene‐expressing esophageal tumors that are infiltrated with activated T cells.