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Targeting tumor vasculature with novel Listeria-based vaccines directed against CD105

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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.

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Conflict of interest

Yvonne Paterson wishes to disclose that she has a financial interest in Advaxis, a vaccine and therapeutic company that has licensed or has an option to license all patents from the University of Pennsylvania that concern the use of Listeria monocytogenes or Listerial products as vaccines.

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Author notes

  1. Matthew Seavey

    Present address: Cephalon, Inc., 145 Brandywine Pkwy, Rm B311/305, West Chester, PA, 19380-4245, USA

Authors and Affiliations

  1. Department of Microbiology, University of Pennsylvania, 323 Johnson Pavilion, Philadelphia, PA, 19104, USA

    Laurence M. Wood, Zhen-Kun Pan, Patrick Guirnalda, Peter Tsai, Matthew Seavey & Yvonne Paterson

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  1. Laurence M. Wood
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  2. Zhen-Kun Pan
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Correspondence to Yvonne Paterson.

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Laurence M. Wood and Zhen-Kun Pan contributed equally to this manuscript.

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262_2011_1002_MOESM1_ESM.eps

Characterization of CD105-specific responses. To characterize the CD105-specific immune response generated by the attenuated Listeria-based CD105 vaccine, Lm-LLO-CD105, 20-mer peptides were generated from the CD105A fragment and assayed for their ability to stimulate IFN-γ secretion by CD8+ T cell enriched splenocytes. a Depiction of 20-mer peptides from the CD105 sequence present in Lm-LLO-CD105A containing possible MHC Class I epitopes. b IFN-γ ELISpot analysis of CD105-specific CD8+ T cell responses in unvaccinated or Lm-LLO-CD105A-vaccinated mice was performed. Briefly, CD8+ T cell enriched splenocytes were co-cultured overnight with irradiated splenocytes loaded with overlapping peptides depicted in Fig. 4A along with positive control H-2kD LLO peptide and either IL-2 or media alone. IFN-γ-producing splenocytes after overnight stimulation were counted by on an ELISpot reader. Supplementary material 1 (EPS 447 kb)

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Wood, L.M., Pan, ZK., Guirnalda, P. et al. Targeting tumor vasculature with novel Listeria-based vaccines directed against CD105. Cancer Immunol Immunother 60, 931–942 (2011). https://doi.org/10.1007/s00262-011-1002-x

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