The Use of Venezuelan Equine Encephalitis Replicons Encoding the Her-2/neu Tumor Associated Antigen for the Prevention and Treatment of Breast Cancer
Abstract
Overexpression and amplification of the Her-2/neu proto-oncogene has been implicated in the development of aggressive human breast cancer. Consequently, Her-2/neu provides a potential target for immunotherapy. Indeed, Her-2/neu specific cytotoxic T lymphocytes (CTL) can be detected in patients with breast and ovarian cancer. Nevertheless, the observed response to Her-2/neu is inadequate to prevent tumor progression. Our overall goal is to determine whether genetic vaccination is a feasible strategy to enhance Her-2/neu specific T cell activity, and in turn prevent and/or treat breast cancer. Specifically, we will employ a novel in vivo gene transfer system based on the Venezuelan Equine Encephalitis (VEE) virus. VEE is an alphavirus which has a number of properties that make it especially well suited for tumor antigen vaccination. The most salient of these is the observation that VEE preferentially infects dendritic cells (DC) in vivo. DC are known to be potent antigen presenting cells capable of efficiently activating naive CD4 and CD8+ T cells. Our approach is to establish VEE based replicons encoding Her-2/neu as well as cytokines, such as IL-12 and IL-18 known to promote CD4+ Th1 and CD8+ CTL activity. To directly determine the therapeutic efficacy of the VEE-based replicons, mice transgenic for the rat Her-2/neu gene (FVB/neu) which develop spontaneous focal mammary tumors with subsequent pulmonary metastasis will be employed. Additionally, FVB/neu mice bred to mice transgenic for the human major histocompatibility complex (MHC) class I molecule HLA-A2.l (FVB/neu/A2-K(sup b)) will be used to examine the immunogenicity of Her-2/neu derived peptides which may have clinical relevance.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADA406098
Entities
People
- Brian R. Long
- Roland M. Tisch
Organizations
- University of North Carolina at Chapel Hill