A novel human Her-2/neu chimeric molecule expressed by Listeria monocytogenes can elicit potent HLA-A2 restricted CD8-positive T cell responses and impact the growth and spread of Her-2/neu-positive breast tumors.
OBJECTIVE
The aim of this study was to efficiently design a novel vaccine for human Her-2/neu-positive (hHer-2/neu) breast cancer using the live, attenuated bacterial vector Listeria monocytogenes.


METHODS
Three recombinant L. monocytogenes-based vaccines were generated that could express and secrete extracellular and intracellular fragments of the hHer-2/neu protein. In addition, we generated a fourth construct fusing selected portions of each individual fragment that contained most of the human leukocyte antigen (HLA) epitopes as a combination vaccine (L. monocytogenes-hHer-2/neu chimera).


RESULTS
Each individual vaccine was able to either fully regress or slow tumor growth in a mouse model for Her-2/neu-positive tumors. All three vaccines could elicit immune responses directed toward human leukocyte antigen-A2 epitopes of hHer-2/neu. The L. monocytogenes-hHer-2/neu chimera was able to mimic responses generated by the three separate vaccines and prevent spontaneous outgrowth of tumors in an autochthonous model for Her-2/neu-positive breast cancer, induce tumor regression in transplantable models, and prevent seeding of experimental lung metastases in a murine model for metastatic breast cancer.


CONCLUSIONS
This novel L. monocytogenes-hHer-2/neu chimera vaccine proves to be just as effective as the individual vaccines but combines the strength of all three in a single vaccination. These encouraging results support future clinical trials using this chimera vaccine and may be applicable to other cancer types expressing the Her-2/neu molecule such as colorectal and pancreatic cancer.
Seavey
Matthew M
MM
Department of Microbiology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA.
Pan
Zhen-Kun
ZK
Maciag
Paulo C
PC
Wallecha
Anu
A
Rivera
Sandra
S
Paterson
Yvonne
Y
Shahabi
Vafa
V
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D018734:Genes, erbB-2; D005822:Genetic Vectors; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D008089:Listeria monocytogenes / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000276:immunology; D014614:Vaccines, Synthetic / Q000627:therapeutic use*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D014614:Vaccines, Synthetic