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Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grant 5RO1CA109253-03. M.M.S. and N.A.-R. were supported by Training Grant T32CA09140, "The Immunobiology of Normal and Neoplastic Lymphocytes."
2 Current address: Advaxis, North Brunswick, NJ 08902.
3 Current address: Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905.
4 Current address: University of Maryland, 16 South Eutaw Street, Suite 500, Baltimore, MD 21201.
5 Address correspondence and reprint requests to Dr. Yvonne Paterson, Department of Microbiology, 323 Johnson Pavilion, 36th Street and Hamilton Walk, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6076. E-mail address: yvonne{at}mail.med.upenn.edu
6 Abbreviations used in this paper: Lm, Listeria monocytogenes; DAPI, 4',6'-diamidino-2-phenylindole; Flk-1, fetal liver kinase-1; HIF-1
, hypoxia-inducible factor-1; LLO, listeriolysin-O; MVD, microvascular density; PEST, proline, glutamine acid, serine, threonine-rich; TIL, tumor-infiltrating lymphocyte; VEGF, vascular endothelial growth factor.
7 The online version of this article contains supplemental material.
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