Advaxis will develop a novel Listeria monocytogenes based vaccine against the human HER-2/neu protein that will be a safe and effective therapeutic vaccine for the treatment of HER-2/neu overexpressing breast carcinomas. Breast cancer, the most common type of cancer in women, is a complex disease with no single causative agent or event. There are several tumor-associated antigens associated with breast cancer. Of these, the HER-2/neu oncogene product is of particular interest because it is overexpressed in approximately one-third of breast adenocarcinomas and is associated with metastatic disease and poor prognosis. Listeria monocytogenes, a facultative intracellular bacterium that infects and proliferates in the cytoplasm of a number of antigen presenting cells has been identified as a therapeutic vaccine vector. These vectors have proven to be powerful in boosting cell mediated immune responses in a number of disease models such as HIV infection and cancer. We propose to take the novel approach of generating L. monocytogenes-based vaccines against the endogenously expressed human gene, the HER-2/neu tumor associated-antigen. We propose to do this in a vector that meets FDA guidelines in that it will not contain any antibiotic resistance genes. We will demonstrate tumor control in 2 FVB mouse models for breast cancer. Furthermore, we will demonstrate that these vaccines induce specific CD8+ T cell responses against the HER-2/neu antigen. Specifically, this Phase I proposal will generate attenuated recombinant L. monocytogenes vaccine vectors that contain no antibiotic resistance genes and will secrete detectable levels of LLO-HER-2/neu fusion proteins (LmDA(-)-LLO-HER-2/neu). Five different constructs containing the Human HER-2/neu gene fragments will be generated, each one containing a different fragment of the p185 human HER-2/neu extracellular or intracellular domain (LmDA(-)-LLO-ECI, LmDA(-)-LLO-EC2, LmDA(-)-LLO-EC3, LmDA(-)- LLO-IC1, LmDA(-)-LLO-IC2). Additionally, we propose to demonstrate the ability of each of these constructs to induce a HER-2/neu specific CD8+ T cell response in the HLA-A2 transgenic mice. This work will demonstrate the utility of the L. monocytogenes-based vaccines, thus setting the stage for further development of a breast cancer therapeutic that can be used in humans. ? ? ? ?
| Seavey, Matthew M; Pan, Zhen-Kun; Maciag, Paulo C et al. (2009) A novel human Her-2/neu chimeric molecule expressed by Listeria monocytogenes can elicit potent HLA-A2 restricted CD8-positive T cell responses and impact the growth and spread of Her-2/neu-positive breast tumors. Clin Cancer Res 15:924-32 |
