Article

Anti-Angiogenesis immunotherapy induces epitope spreading to Her-2/neu resulting in breast tumor immunoediting

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Breast Cancer: Targets and Therapy 01/2009; 1:19-30. DOI: 10.2147/BCTT.S6689
Source: PubMed

ABSTRACT

Targeting tumors using cancer vaccine-therapeutics has several advantages including the induction of long-term immunity, prime boost strategies for additional treatments and reduced side effects compared to conventional chemotherapeutics. However, one problem in targeting tumor antigens directly is that this can lead to antigen loss or immunoediting. We hypothesized that directing the immune response to a normal cell type required for tumor growth and survival could provide a more stable immunotherapeutic target. We thus examined the ability of an anti-angiogenesis, Listeria monocytogenes (Lm) based vector to deliver extracellular and intracellular fragments of the mouse VEGFR2/Flk-1 molecule, Lm-LLO-Flk-E1 and Lm-LLO-Flk-I1 respectively, in an autochthonous model for Her-2/neu(+) breast cancer. We found that these vaccines could cause epitope spreading to the endogenous tumor protein Her-2/neu and significantly delay tumor onset. However, tumors that grew out overtime accumulated mutations in the Her-2/neu molecule near or within CTL epitopes. We show here for the first time how an anti-angiogenesis immunotherapy can be used to delay the onset of a spontaneous tumor through epitope spreading and determine a possible mechanism of how immunoediting of an endogenous tumor protein can allow for tumor escape and outgrowth in an autochthonous mouse model for Her-2/neu(+) breast cancer.

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Available from: ncbi.nlm.nih.gov
    • "Lm-based vaccines targeting TAAs have demonstrated promise in numerous preclinical studies, however, the appearance of tumor immunoediting and tumor immune escape, likely due in part to the genetic instability of tumor cells (Cahill et al., 1998), has presented a challenge (Singh and Paterson, 2007a). Therefore, focus turned to targeting TAAs expressed by cell types believed to have greater genetic stability such as the tumor-associated vascular endothelial cells (Seavey and Paterson, 2009; Wood et al., 2011). Tumor-associated vascular endothelial cells have been successfully targeted with passive immunity to treat cancer for several years but a CTL-mediated approach is still lacking (Kim et al., 1993). "

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