An anti-vascular endothelial growth factor receptor 2/fetal liver kinase-1 Listeria monocytogenes anti-angiogenesis cancer vaccine for the treatment of primary and metastatic Her-2/neu+ breast tumors in a mouse model.
Thirty years after angiogenesis was shown to play an enabling role in cancer, modern medicine is still trying to develop novel compounds and therapeutics to target the tumor vasculature. However, most therapeutics require multiple rounds of administration and can have toxic side effects. In this study, we use anti-angiogenesis immunotherapy to target cells actively involved in forming new blood vessels that support the growth and spread of breast cancer. Targeting a central cell type involved in angiogenesis, endothelial cells, we immunized against host vascular endothelial growth factor receptor 2 to fight the growth of Her-2/neu(+) breast tumors. Using the bacterial vector, Listeria monocytogenes (Lm), we fused polypeptides from the mouse vascular endothelial growth factor receptor 2 molecule (fetal liver kinase-1) to the microbial adjuvant, listeriolysin-O, and used Lm to deliver the Ags and elicit potent antitumor CTL responses. Lm-listeriolysin-O-fetal liver kinase-1 was able to eradicate some established breast tumors, reduce microvascular density in the remaining tumors, protect against tumor rechallenge and experimental metastases, and induce epitope spreading to various regions of the tumor-associated Ag Her-2/neu. Tumor eradication was found to be dependent on epitope spreading to HER-2/neu and was not solely due to the reduction of tumor vasculature. However, vaccine efficacy did not affect normal wound healing nor have toxic side effects on pregnancy. We show that an anti-angiogenesis vaccine can overcome tolerance to the host vasculature driving epitope spreading to an endogenous tumor protein and drive active tumor regression.
Seavey
Matthew M
MM
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Maciag
Paulo C
PC
Al-Rawi
Nada
N
Sewell
Duane
D
Paterson
Yvonne
Y
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006360:Heat-Shock Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006460:Hemolysin Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
D020533:Angiogenesis Inhibitors; D001427:Bacterial Toxins; D019496:Cancer Vaccines; D006131:Growth Inhibitors; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; C038705:hlyA protein, Listeria monocytogenes