title: Targeting tumor vasculature with novel Listeria-based vaccines directed against CD105.
abstract: The FDA approval of bevacizumab (Avastin®, Genentech/Roche), a monoclonal antibody raised against human VEGF-A, as second-line therapy for colon and lung carcinoma validated the approach of targeting human tumors with angiogenesis inhibitors. While the VEGF/VEGFR pathway is a viable target for anti-angiogenesis tumor therapy, additional targets involved in tumor neovascularization have been identified. One promising target present specifically on tumor vasculature is endoglin (CD105), a member of the TGF-β receptor complex expressed on vascular endothelium and believed to play a role in angiogenesis. Monoclonal antibody therapy and preventive vaccination against CD105 has met with some success in controlling tumor growth. This report describes the in vivo proof-of-concept studies for two novel therapeutic vaccines, Lm-LLO-CD105A and Lm-LLO-CD105B, directed against CD105 as a strategy to target neovascularization of established tumors. Listeria-based vaccines directed against CD105 lead to therapeutic responses against primary and metastatic tumors in the 4T1-Luc and NT-2 mouse models of breast cancer. In a mouse model for autochthonous Her-2/neu-driven breast cancer, Lm-LLO-CD105A vaccination prevented tumor incidence in 20% of mice by week 58 after birth while all control mice developed tumors by week 40. In comparison with previous Listeria-based vaccines targeting tumor vasculature, Lm-LLO-CD105A and Lm-LLO-CD105B demonstrated equivalent or superior efficacy against two transplantable mouse models of breast cancer. Support is provided for epitope spreading to endogenous tumor antigens and reduction in tumor vascularity after vaccination with Listeria-based CD105 vaccines. Reported here, these CD105 therapeutic vaccines are highly effective in stimulating anti-angiogenesis and anti-tumor immune responses leading to therapeutic efficacy against primary and metastatic breast cancer.
authors: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Laurence M
authors: LM
authors: Wood
authors: Zhen-Kun
authors: ZK
authors: Pan
authors: Patrick
authors: P
authors: Guirnalda
authors: Peter
authors: P
authors: Tsai
authors: Matthew
authors: M
authors: Seavey
authors: Yvonne
authors: Y
authors: Paterson
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D000071063:Endoglin; D005260:Female; D006801:Humans; D007167:Immunotherapy; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008087:Listeria / Q000235:genetics / Q000276:immunology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta; D015996:Survival Rate
chemical_list: D020533:Angiogenesis Inhibitors; D019496:Cancer Vaccines; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta