Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients.

BACKGROUND: Cholesteryl pullulan (CHP) is a novel antigen delivery system for cancer vaccines. This study evaluated the safety, immune responses and clinical outcomes of patients who received the CHP-NY-ESO-1 complex vaccine, Drug code: IMF-001. METHODS: Patients with advanced/metastatic esophageal cancer were enrolled and subcutaneously vaccinated with either 100 µg or 200 µg of NY-ESO-1 protein complexed with CHP. The primary endpoints were safety and humoral immune responses, and the secondary endpoint was clinical efficacy. RESULTS: A total of 25 patients were enrolled. Thirteen and twelve patients were repeatedly vaccinated with 100 µg or 200 µg of CHP-NY-ESO-1 with a median of 8 or 9.5 doses, respectively. No serious adverse events related to the vaccine were observed. Three out of 13 patients in the 100-µg cohort and 7 out of 12 patients in the 200-µg cohort were positive for anti-NY-ESO-1 antibodies at baseline. In the 100-µg cohort, an antibody response was observed in 5 out of 10 pre-antibody-negatives patients, and the antibody levels were augmented in 2 pre-antibody-positive patients after vaccination. In the 200-µg cohort, all 5 pre-antibody-negative patients became seropositive, and the antibody level was amplified in all 7 pre-antibody-positive patients. No tumor shrinkage was observed. The patients who received 200 µg of CHP-NY-ESO-1 survived longer than patients receiving 100 µg of CHP-NY-ESO-1, even those who exhibited unresponsiveness to previous therapies or had higher tumor burdens. CONCLUSIONS: The safety and immunogenicity of CHP-NY-ESO-1 vaccine were confirmed. The 200 µg dose more efficiently induced immune responses and suggested better survival benefits. (Clinical trial registration number NCT01003808).

Preclinical safety pharmacology study of a novel protein-based cancer vaccine CHP-NY-ESO-1.

CHP-NY-ESO-1 is a novel therapeutic cancer vaccine consisting of a recombinant protein of cancer antigen NY-ESO-1 and a polysaccharide-based delivery system, cholesteryl pullulan. A pilot clinical study of CHP-NY-ESO-1 in cancer patients was previously conducted, and the adverse events related to this drug were observed to be limited to skin reactions at injection sites. To further establish the safety of CHP-NY-ESO-1, we studied the effects of its subcutaneous injection on vital functions such as the central nervous system, cardiovascular system and respiratory system using preclinical animal models. The effects of CHP-NY-ESO-1 on the cardiovascular system were investigated in dogs using a telemetry system for blood pressure and heart rate and the Holter monitoring for ambulatory electrocardiograms. No drug-related changes were observed in these parameters. The effect of CHP-NY-ESO-1 on the hERG-dependent potassium currents was also examined using in vitro cultured cell system, and no inhibition of hERG currents was observed. The effects of CHP-NY-ESO-1 on the central nervous system were examined in rats using functional observational battery method, and no drug-related changes were observed in home cage observations, open field observations, hand held observations, and perception and motor function observations. The effect of CHP-NY-ESO-1 on the respiratory system was investigated in rats by measuring tidal volume, minute volume and respiratory rate using whole-body plethysmograph method, and no significant changes were found in these parameters. These results indicate that CHP-NY-ESO-1 would not have any pharmacological effects on vital functions and support the safety of this cancer vaccine for clinical use.