Development of a live and highly attenuated Listeria monocytogenes-based vaccine for the treatment of Her2eu-overexpressing cancers in human

摘要

A chimeric human Her2eu gene (ChHer2) harboring most of the known major histocompatibility complex class I epitopes of the HER2eu oncogene was expressed as a fusion protein to a non-hemolytic fragment of listeriolysin O (LLO), by the highly attenuated Listeria vector LmddA, which lacks antibiotic selection markers and the ability to spread from cell-to-cell. This construct (ADXS31–164) was tested for immunogenicity and anti-tumor effects in mice. Despite being highly attenuated, ADXS31–164 proved to be efficacious in breaking immune tolerance toward the HER2eu self-antigen. ADXS31–164 elicited strong T-cell immune responses in experimental animals. In tumors, ADXS31–164 caused a reduction in regulatory T cells (Treg) accompanied by an increase in the CD8+/Treg ratio. Comparison of this vaccine with the conventional antibiotic resistant Listeria vector (Lm-LLO-ChHer2) shows that ADXS31–164 is more efficacious in delaying tumor growth in Her2eu transgenic animals. Because of its well-defined attenuation mechanism and independence from antibiotic selection markers, ADXS31–164 is potentially more suitable for human use. These results support the future clinical development of this vaccine for the treatment of HER2eu-overexpressing malignancies, such as breast, colorectal and pancreatic cancers.