Development of a live and highly attenuated Listeria monocytogenes-based vaccine for the treatment of Her2/neu-overexpressing cancers in human.
A chimeric human Her2/neu gene (ChHer2) harboring most of the known major histocompatibility complex class I epitopes of the HER2/neu 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 HER2/neu 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 Her2/neu 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 HER2/neu-overexpressing malignancies, such as breast, colorectal and pancreatic cancers.
Shahabi
V
V
Advaxis Inc., New Brunswick, NJ 08902, USA.
Seavey
M M
MM
Maciag
P C
PC
Rivera
S
S
Wallecha
A
A
D000818:Animals; D001943:Breast Neoplasms / Q000517:prevention & control; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008089:Listeria monocytogenes; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014613:Vaccines, Attenuated